Toll-like receptor 4: Difference between revisions

TLR4
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	4G8A, 2Z62, 2Z63, 2Z65, 2Z66, 3FXI, 3UL7, 3UL8, 3UL9, 3ULA
Identifiers
Aliases	TLR4, ARMD10, CD284, TLR-4, TOLL, toll like receptor 4
External IDs	OMIM: 603030; MGI: 96824; HomoloGene: 41317; GeneCards: TLR4; OMA:TLR4 - orthologs
Gene location (Human)
Chr.	Chromosome 9 (human)
End	117,724,735 bp
Gene location (Mouse)
Chr.	Chromosome 4 (mouse)
End	66,848,521 bp
RNA expression pattern
	Top expressed in
	monocyte; ; Achilles tendon; ; blood; ; bone marrow; ; trabecular bone; ; spleen; ; granulocyte; ; right lung; ; gallbladder; ; bone marrow cells;
	Top expressed in
	lumbar spinal ganglion; ; aortic valve; ; ascending aorta; ; granulocyte; ; decidua; ; epithelium of stomach; ; stroma of bone marrow; ; endothelial cell of lymphatic vessel; ; cervix; ; mucous cell of stomach;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	lipopolysaccharide immune receptor activity; lipopolysaccharide binding; protein binding; transmembrane signaling receptor activity;
Cellular component	cytoplasm; membrane; perinuclear region of cytoplasm; cell surface; integral component of membrane; plasma membrane; endosome membrane; intrinsic component of plasma membrane; integral component of plasma membrane; lipopolysaccharide receptor complex; external side of plasma membrane;
Biological process	positive regulation of MHC class II biosynthetic process; positive regulation of JNK cascade; TRIF-dependent toll-like receptor signaling pathway; cellular response to mechanical stimulus; positive regulation of interleukin-8 production; positive regulation of ERK1 and ERK2 cascade; T-helper 1 type immune response; positive regulation of platelet activation; positive regulation of interleukin-1 production; positive regulation of stress-activated MAPK cascade; positive regulation of NLRP3 inflammasome complex assembly; positive regulation of interleukin-12 production; positive regulation of interferon-alpha production; I-kappaB phosphorylation; positive regulation of nitric-oxide synthase biosynthetic process; positive regulation of B cell proliferation; defense response to bacterium; positive regulation of interleukin-6 production; activation of innate immune response; positive regulation of tumor necrosis factor production; negative regulation of tumor necrosis factor production; innate immune response; negative regulation of interleukin-17 production; I-kappaB kinase/NF-kappaB signaling; positive regulation of interferon-beta production; positive regulation of inflammatory response; toll-like receptor 4 signaling pathway; positive regulation of macrophage cytokine production; positive regulation of interleukin-10 production; immune system process; astrocyte development; intestinal epithelial structure maintenance; positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway; response to lipopolysaccharide; cellular response to lipoteichoic acid; positive regulation of NF-kappaB transcription factor activity; immune response; negative regulation of interleukin-23 production; regulation of inflammatory response; positive regulation of chemokine production; lipopolysaccharide-mediated signaling pathway; detection of fungus; positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway; negative regulation of interferon-gamma production; response to bacterium; negative regulation of osteoclast differentiation; B cell proliferation involved in immune response; positive regulation of nitric oxide biosynthetic process; negative regulation of interleukin-6 production; positive regulation of interferon-gamma production; nitric oxide production involved in inflammatory response; MyD88-dependent toll-like receptor signaling pathway; regulation of dendritic cell cytokine production; positive regulation of gene expression; negative regulation of ERK1 and ERK2 cascade; positive regulation of I-kappaB kinase/NF-kappaB signaling; macrophage activation; detection of lipopolysaccharide; cellular response to lipopolysaccharide; positive regulation of lymphocyte proliferation; positive regulation of transcription by RNA polymerase II; MyD88-independent toll-like receptor signaling pathway; signal transduction; inflammatory response; defense response to Gram-negative bacterium; toll-like receptor signaling pathway; necroptosis; apoptotic signaling pathway; negative regulation of MyD88-independent toll-like receptor signaling pathway;
	Sources:Amigo / QuickGO
Orthologs
	7099
	21898
	ENSG00000136869
	ENSMUSG00000039005
	O00206
	Q9QUK6
	NM_138557; NM_003266; NM_138554; NM_138556
	NM_021297
	NP_003257; NP_612564; NP_612567
	NP_067272
	Wikidata
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Revision as of 16:48, 20 February 2024

Toll-like receptor 4 (TLR4), also designated as CD284 (cluster of differentiation 284), is a transmembrane protein of approximately 95 kDa that is encoded by the TLR4 gene.

TLR4 belongs to the toll-like receptor family which is representative of the pattern recognition receptors (PRR), so named for their ability to recognize evolutionarily conserved components of microorganisms (bacteria, viruses, fungi and parasites) called pathogen-associated molecular patterns (PAMPs). The recognition of a PAMP by a PRR triggers rapid activation of the innate immunity essential to fight infectious diseases.^[5]

TLR4 is expressed in immune cells mainly of myeloid origin, including monocytes, macrophages and dendritic cells (DC).^[6] It is also expressed at a lower level on some non-immune cells, including epithelium, endothelium, placental cells and beta cells in Langerhans islets. Most myeloid cells express also high amounts of plasma membrane-anchored CD14, which facilitates the activation of TLR4 by LPS and controls the subsequent internalization of the LPS-activated TLR4 important for receptor signaling and degradation.^[7]^[8]

The main ligands for TLR4 are lipopolysaccharides (LPS), the major components of the outer membrane of Gram-negative bacteria and some Gram-positive bacteria. TLR4 can also be activated by endogenous compounds called damage-associated molecular patterns (DAMPs), including high mobility group box protein 1 (HMGB1), S100 proteins, or histones. These compounds are released during tissue injury and by dying or necrotic cells ^[9]^[10]^[11]^[12]^[13].

Function

The first function described for TLR4 was the recognition of exogenous molecules from pathogens (PAMPs), in particular LPS molecules from gram-negative bacteria ^[14]. As pattern recognition receptor, TLR4 plays a fundamental role in pathogen recognition and activation of innate immunity which is the first line of defense against invading micro-organisms. During infection, TLR4 responds to the LPS present in tissues and the bloodstream and triggers pro-inflammatory reactions facilitating eradication of the invading bacteria ^[15].

TLR4 is also involved in the recognition of endogenous DAMP molecules leading to different signaling outcomes than PAMPs, both quantitatively and qualitatively ^[16]^[17]. Through TLR4, DAMPs can activate TLR4 in non-infectious conditions to induce tissue repair and the activation of proinflammatory responses ^[9]^[10]^[11]^[12]^[13]. Generally, inflammation has a protective role. It is a complex and coordinated process followed by the induction of resolution pathways that restore tissue integrity and function. However, in some cases, an excessive and/or poorly regulated inflammatory response to DAMPs can be detrimental to the organism, accelerating the development or progression of pathologies such as a number of cancers and neurodegenerative diseases (as discussed below).

TLR4 binds LPS with the help of LPS-binding protein (LBP) and CD14, and an indispensable contribution of the MD-2 protein stably associated with the extracellular fragment of the receptor ^[18]. TLR4 signaling responds to signals by forming a complex using an extracellular leucine-rich repeat domain (LRR) and an intracellular toll/interleukin-1 receptor (TIR) domain. LPS stimulation induces a series of interactions with several accessory proteins which form the TLR4 complex on the cell surface. LPS recognition is initiated by an LPS binding to an LBP protein. This LPS-LBP complex transfers the LPS to CD14 which is a glycosylphosphatidylinositol-anchored membrane protein that binds the LPS-LBP complex and facilitates the transfer of LPS to MD-2 protein, which is associated with the extracellular domain of TLR4. LPS binding promotes the dimerization of TLR4/MD-2 complex. The conformational changes of the TLR4 induce the recruitment of intracellular adaptor proteins containing the TIR domain which is necessary to activate the downstream signaling pathway.

The binding of an LPS molecule to the TLR4/MD-2 complex involves acyl chains and phosphate groups of lipid A, the conserved part of LPS and the main inducer of pro-inflammatory responses to LPS ^[19]^[20].

TLR4 activation and response to LPS is greatly influenced by the polysaccharide domain and the molecular structure of Lipid A moiety of the LPS molecules. Hexa-acylated and diphosphorylated LPS, like Escherichia coli LPS (O111:B4), is one of the most potent agonists of TLR4 whereas under-acylated LPS and dephosphorylated LPS species have a weaker pro-inflammatory activity especially in human cells ^[21]. Structural determinants of this phenomenon are found in the TLR4/MD-2 complex and also in CD14 protein ^[22]^[23]. The polysaccharide portion covalently bound to lipid A plays also and indispensable role in TLR4 activation through CD14/TLR4/MD-2 ^[24]. However, It was demonstrated that the lipid A moiety alone was less active than the full LPS molecule ^[25].

Signaling

Unlike all the other TLRs, TLR4 stimulation triggers two signaling pathways called the MyD88-dependent and the TRIF-dependent one after the adaptor proteins involved in their induction ^[26]^[27]. The MyD88-dependent signaling is triggered by TLR4 localized to the plasma membrane, while the TRIF-dependent one by the TLR4 internalized in endosomes.

These signaling pathways lead to the production of two sets of cytokines. The MyD88-dependent pathway induces the production of pro-inflammatory cytokines while TRIF-dependent pathway induces the production of type I interferons and chemokines. The molecular structure of TLR4 ligands (LPS or DAMPs), as well as their complexation with proteins or lipids, greatly influence the action of these TLR4-related signaling pathways, leading to different cytokine balances.

MyD88 – dependent pathway

The MyD88-dependent pathway is regulated by two adaptor-associated proteins: Myeloid Differentiation Primary Response Gene 88 (MyD88) and TIR Domain-Containing Adaptor Protein (TIRAP). TIRAP-MyD88 regulates early NF-κβ activation and production of proinflammatory cytokines, such as IL-12.^[5] MyD88 signaling involves the activation of IL-1 Receptor-Associated Kinases (IRAKs) and the adaptor molecules TNF Receptor-Associated Factor 6 (TRAF6). TRAF6 induces the activation of TAK1 (Transforming growth factor-β-Activated Kinase 1) that leads to the activation of MAPK cascades (Mitogen-Activated Protein Kinase) and IKK (IκB Kinase). IKKs' signaling pathway leads to the induction of the transcription factor NF-κB, while activation of MAPK cascades lead to the activation of another transcription factor AP-1. Both of them have a role in the expression of proinflammatory cytokines.^[28] The activation of NF-κB via TAK-1 is complex, and it starts by the assembly of a protein complex called the signalosome, which is made of a scaffolding protein, called NEMO. The protein complex is made from two different κB kinases, called IKKα and IKKβ. This causes the addition of a small regulatory protein to the signalosome called ubiquitin, that acts to initiate the release of the NF-κB protein, which coordinates translocation in the nucleus of cytokines.^[29] Collectively, the MyD88-dependent signaling pathway induces the expression of genes encoding pro-inflammatory mediators, such as tumor necrosis factor α (TNF-α), interleukin (IL)-6, and type III interferons (IFNλ1/2) and participates in the production of anti-inflammatory mediators, like IL-10 helping to terminate the inflammation ^[30]^[31]^[32].

TRIF – dependent pathway

The TRIF-dependent pathway involves the internalization of TLR4 in endosomes and the recruitment of the adaptor proteins TIR-domain-containing adaptor inducing interferon-β (TRIF) and TRIF-related Adaptor Molecule (TRAM). TRAM-TRIF signals activate the ubiquitin ligase TRAF3 followed by the activation of non-canonical IKK kinases: TANK binding kinase 1 (TBK1) and IKKε. TBK1 phosphorylates the pLxIS consensus motif of TRIF that is necessary to recruit interferon regulatory factor (IRF) 3. IRF3 is also phosphorylated by TBK1 and then dissociates from TRIF, dimerizes and translocates to the nucleus ^[33]. Finally, IRF3 induces the expression of genes encoding type I IFN, the chemokine CCL5/ RANTES and interferon-regulated genes as that encoding the chemokine CXCL10/IP-10 ^[34]^[35]^[36]^[37].

Immune cell activation

TLR4 activation by LPS on innate immune cells such as macrophages and DC induces the secretion of both pro-inflammatory and type I interferon cytokines and chemokines. It also induces the stimulation of antigen presentation and upregulation of costimulatory molecules such as CD40, CD80 and CD86 on the cell surface which are required for antigen presentation for T lymphocytes ^[38]^[39]. So, in addition to innate immune cell stimulation, activation of TLR4 by LPS enables the onset, the recruitment, the polarization and the maintenance of effective and long-lasting T-cell responses ^[40]^[41]. However, significant differences were found in the signaling pathways leading to this phenomenon. In macrophages, the upregulation depends strictly on the TRIF-dependent pathway, whereas in DC both the MyD88- and TRIF-dependent ones are involved ^[42]^[43]^[44]^[45]. The increased cell surface presence of the costimulatory molecules and also of MHC II is a hallmark of DC maturation required for antigen presentation by these cells ^[46]. Beside the contribution to the upregulation of MHC II and costimulatory molecules, the TLR4-triggered MyD88-dependent signaling in DC also induces production of cytokines leading to Th1 cell polarization and also facilitates fusion of MHC I-bearing recycling endosomes with phagosomes to allow cross-presentation of antigens during infection ^[47].

The impact of TLR4 activation on the innate and adaptive immune system explains why TLR4 agonists, such as LPS derivatives, have been developed as vaccine adjuvants. Among them is monophosphoryl lipid A (MPL), a detoxified LPS, which has been approved as a vaccine adjuvant in five human vaccines ^[48]^[49]^[50].

Evolutionary history and polymorphism

TLR4 originated when TLR2 and TLR4 diverged about 500 million years ago near the beginning of vertebrate evolution.^[51] Sequence alignments of human and great ape TLR4 exons have demonstrated that not much evolution has occurred in human TLR4 since our divergence from our last common ancestor with chimpanzees; human and chimp TLR4 exons only differ by three substitutions while humans and baboons are 93.5% similar in the extracellular domain ^[52]. Notably, humans possess a greater number of early stop codons in TLR4 than great apes; in a study of 158 humans worldwide, 0.6% had a nonsense mutation ^[53]^[54]. This suggests that there are weaker evolutionary pressures on the human TLR4 than on our primate relatives. The distribution of human TLR4 polymorphisms matches the out-of-Africa migration, and it is likely that the polymorphisms were generated in Africa before migration to other continents ^[54]^[55].

Various single nucleotide polymorphisms (SNPs) of TLR4 have been identified in humans . For some of them, an association with increased susceptibility to Gram-negative bacterial infections or faster progression and a more severe course of sepsis in critically ill patients was reported.However, they are very rare, and their frequency varies according to ethnic origin. The 2 predominant SNPs are Asp299Gly and Thr399Ile, with a frequency of <10% in the Caucasian population and even lower in the Asian population ^[56]. These two SNPs are missense mutations, thus associated with a loss of function, which may explain their negative impact on infection control. Studies have indeed shown that TLR4 D299G SNP limits the response to LPS by compromising MyD88 and TRIF recruitment to TLR4, and thus cytokine secretion, but without affecting TLR4 expression ^[57]^[58]. Structural analyses of human TLR4 with SNP D299G suggest that this amino acid change affects van der Waals interaction and hydrogen bonding in leucine-rich repeats, modulating its surface properties which may affect LPS ligand binding to TLR4 ^[59].

Clinical significance

TLR4 has been reported to play both friend and foe in a variety of human diseases, such as bacterial infections and cancers. This dual role of TLR4 depends on the tyintensity, duration and site (surface or endosome) of its activation, its polymorphism and the balance of activation of signaling pathways (MyD88 vs. TRIF).

Infectious diseases

TLR4 play a central role in the control of bacterial infections through the recognition of LPS molecules from gram-negative, and some gram-positive, bacteria ^[60]. During infections, TLR4s on innate immunity cells are activated by LPS molecules present in tissues and the bloodstream. This activates innate immunity, the first line of defense against invading microorganisms, and triggers pro-inflammatory responses that facilitate the eradication of invading bacteria ^[61]. Generally, inflammation has a protective role. It is a complex and coordinated process followed by the induction of resolution pathways that restore tissue integrity and function. However, in some cases, exaggerated and uncontrolled inflammation triggered by TLR4 during infection can lead to sepsis and septic shock ^[62]. Infections with Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa are the prevailing causes of severe sepsis in humans.Some studies have linked TLR4 polymorphisms (Asp299Gly and Thr399Ile SNPs) to an increased susceptibility to sepsis due to gram-negative infection but other studies failed to confirm this ^[63].

In cancer

The role of the TLR4 in the control of cancer progression and in cancer therapy is well documented.

Stimulation of TLR4 by natural derivatives and LPS is well known to induce potent antitumor activity. This anti-tumor activity is linked to the ability of LPS to stimulate innate immunity via TLR4, resulting in the production of pro-inflammatory cytokines and type 1 interferons, and the indirect generation of adaptive anti-tumor responses ^[64]^[65].

The first clues about the efficacy of TLR4 agonists like LPS in cancer immunotherapy was found in the 19th centuries, when bacterial infections were found to induce tumor regressions ^[66]. Later, Dr William Coley showed the therapeutic efficacy of a mixed bacterial vaccine, so-called “Coley’s toxin”, to human cancer ^[67]. Since then, a number of developments have been made in the treatment or prevention of cancer using bacterial mixtures strongly activating TLR4 due to LPS content. The antituberculosis vaccine Bacillus Calmette–Guérin (BCG) was approved by the Federal Drug Administration (FDA) in 1990 for the local treatment of superficial bladder cancer. BCG promotes dendritic cell maturation, and this effect is TLR4 (as well as TLR2) dependent ^[68]. There are also reports on the treatment of oral squamous cell carcinoma, gastric , Head-and-neck and cervical cancers with lyophilized streptococcal preparation OK-432 (Picibanil) ^[69]. The mechanism of action of OK-432 involves TLR4 activation, since OKA-432 does not inhibit tumor growth on TLR4 knockouts as it does on wild-type mice ^[70].

Purified LPS also showed potent anti-tumor efficacy as systemic therapeutic agents in several tumor models ^[71]^[72]. In the 90’s, clinical trials evaluating the intravenous administration of LPS to patients with cancer provided positive results including several cases of disease stabilization and partial responses. However, limiting toxicities at doses in the ng/kg range has been reported which are too low to obtain significant antitumor effects ^[73].

Subsequently, detoxified TLR4 agonists (LPS derivatives) have been produced and evaluated in the clinic. This includes the MPL, a chemically modified LPS which was the first TLR4 agonist to be approved and commercialized by GSK in 5 human vaccines (HPV, Zoster, Hepatitis B, Malaria, RSV). MPL was investigated as an adjuvant for curative anti-tumor vaccines, with the approval of Melacine in Canada for the treatment of patients with malignant melanoma ^[74]. Synthetic LPS derivatives based on dephosphorylated lipid A moiety structures were also developed and confirmed potent adjuvant and antitumor activities as therapeutic agents. In particular, the intratumoral administration of Glucopyranosyl Lipid Adjuvant (GLA-SE/G100), a synthetic detoxified analog of lipid A formulated in a stable emulsion, showed anti-tumor immune responses and tumor regression in patients with Merkel cell carcinoma ^[75], and potent adjuvant activity in phase 2 trials in combination with pembrolizumab in patients with follicular lymphoma ^[76]^[77].

Besides the recognized anti-tumor efficacy of TLR4 activation by LPS, some studies suggest that TLR4 may also contribute to the development of some cancers, (prostate, liver, breast and lung cancers) and may contribute to resistance to paclitaxel chemotherapy in breast cancer ^[78]. Some clinical studies also suggested a potential correlation between TLR4 expression on tumor cells and tumor progression. However, no such effect was reported in the numerous clinical studies conducted with natural LPS or LPS derivatives. On the contrary, in phase 2 studies with GLA, a positive association between baseline TLR4 expression in tumors and the increase of overall response rates has been reported ^[79].

The potential impact of TLR4 on the progression of some cancers was associated with the excessive production of pro-inflammatory cytokines via activation of the TLR4-MyD88/NF-kB signaling pathway ^[80]^[81]^[82]. Several studies showed that this is mediated by the misuse of DAMP signaling by tumor cells ^[83]^[84]^[85].

Many DAMPs are released by dying or necrotic tumor cells and present during cancer progression. DAMPs released from tumor cells can directly activate tumor-expressed TLR4 that induce chemoresistance, migration, invasion, and metastasis. Furthermore, DAMP-induced chronic inflammation in the tumor microenvironment causes an increase in immunosuppressive populations, such as M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) ^[86]. DAMPs, such as HMGB1, S100 proteins, and heat shock proteins (HSPs), were found to strongly activate inflammatory pathways and release IL-1, IL-6, LT-β, IFN-γ, TNF, and transforming growth factor (TGF)-β promoting inflammation, immunosuppression, angiogenesis, and tumor cell proliferation ^[87].

Several studies have evaluated the potential association of this TLR4 polymorphism with cancer risk, but the data are highly conflicting. However, some meta-analyses suggest an association of SNP D299G with gastric, viral-induced and female-specific cancers (cervix, ovary) ^[88].

In neurogenerative diseases

Growing evidence suggests an implication of TLR4 in the development and progression of neurogenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. In the brain, TLR4 is expressed by neurons as well as the non-neuronal glial cells, which include microglia, astrocytes, and oligodendrocytes. TLR4 is expressed primarily by microglia, and to a lesser extent by astrocytes, oligodendrocytes, and neurons ^[89]. Microglia are representatives of the mononuclear phagocyte system in the brain, and TLR4 activation regulates some of their functions, such as phagocytic activity ^[90]^[91].

Activation of microglial TLR4 has been suggested to protect against or slow the development of neurodegenerative diseases, notably by enhancing the clearance of neurotoxic proteins such as Aβ and its aggregates, thanks to increased phagocytic and autophagic activity ^[92].

However, chronic TLR4 activation is believed to be associated with glia-mediated neuronal death due to excessive secretion of pro-inflammatory cytotoxins leading to neuroinflammation, a key factor in the development of many neurodegenerative diseases ^[93]^[94]. In the brain, TLR4 can be activated by various endogenous DAMPs in addition to pathology-associated proteins such as aggregates of amyloid-βpeptides (Aβ) or α-synuclein ^[95]. All these structures bind TLR4 and activate downstream signaling pathways in glia, inducing secretion of reactive oxygen species (ROS) and proinflammatory cytokines such as IL-1β and TNF-α, which can lead to damage and death of neurons ^[96]^[97]^[98]. Neuronal death is accompanied by the release of DAMPs into the extracellular space, which can then further activate TLR4, aggravating neuroinflammation ^[99]. In patients with Alzheimer's disease (AD), the levels of circulating DAMPs like HMGB1 and soluble RAGE, are significantly elevated, which was correlated with the levels of amyloid beta ^[100]. In AD patients, the serum levels of S100B are also intimately related to the severity of the disease ^[101]. The role of the HMGB1-TLR4 axis is very important in the pathogenesis of Parkinson's disease (PD). The serum HMGB1 and TLR4 protein levels were significantly elevated in PD patients and correlated with the PD stages ^[102].

Targeting TLR4 with agonists or antagonists, or modulating its downstream signaling pathways, may have a therapeutic potential in treating neurodegenerative diseases ^[103]. TLR4-specific antagonists could suppress neuroinflammation by reducing overproduction of inflammatory mediators and cytotoxins by glia. However, TLR4 antagonists could have adverse CNS effects by inhibiting phagocytosis by glia, reducing protein clearance, and interfering with myelination ^[104]. Some studies showed that selective TLR4 agonists could be beneficial by upregulating the phagocytic activity of microglia, leading to enhanced clearance of damaged tissue and abnormal protein aggregates associated with several different CNS diseases. Repeated injections of MPL, at doses that are nonpyrogenic, were found to significantly improved AD-related pathology mice ^[105]. MPL led to a significant reduction in Aβ load in the brain, as well as enhanced cognitive function. MPL induced a potent phagocytic response by microglia while triggering a moderate inflammatory reaction. However, adverse effects can be caused by TLR 4 agonists inducing secretion of inflammatory mediators. Studies therefore suggested that TLR4 agonists that selectively activate the TRIF signaling pathway could be highly beneficial in the treatment of neurodegenerative disorders by increasing glial cell phagocytic activity without significantly increasing glial cytokines and cytotoxins ^[106].

Drugs targeting TLR4

Toll-like receptor 4 has been shown to be important for the long-term side-effects of opioid analgesic drugs. Various μ-opioid receptor ligands have been tested and found to also possess action as agonists or antagonists of TLR4, with opioid agonists such as (+)-morphine being TLR4 agonists, while opioid antagonists such as naloxone were found to be TLR4 antagonists. Activation of TLR4 leads to downstream release of inflammatory modulators including TNF-α and Interleukin-1, and constant low-level release of these modulators is thought to reduce the efficacy of opioid drug treatment with time, and be involved in both the development of tolerance to opioid analgesic drugs,^[107]^[108] and in the emergence of side-effects such as hyperalgesia and allodynia that can become a problem following extended use of opioid drugs.^[109]^[110] Drugs that block the action of TNF-α or IL-1β have been shown to increase the analgesic effects of opioids and reduce the development of tolerance and other side-effects,^[111]^[112] and this has also been demonstrated with drugs that block TLR4 itself.

The response of TLR4 to opioid drugs has been found to be enantiomer-independent, so the "unnatural" enantiomers of opioid drugs such as morphine and naloxone, which lack affinity for opioid receptors, still produce the same activity at TLR4 as their "normal" enantiomers.^[113]^[114] This means that the unnatural enantiomers of opioid antagonists, such as (+)-naloxone, can be used to block the TLR4 activity of opioid analgesic drugs, while leaving the μ-opioid receptor mediated analgesic activity unaffected.^[115]^[114]^[116] This may also be the mechanism behind the beneficial effect of ultra-low dose naltrexone on opioid analgesia.^[117]

Morphine causes inflammation by binding to the protein lymphocyte antigen 96, which, in turn, causes the protein to bind to Toll-like receptor 4 (TLR4).^[118] The morphine-induced TLR4 activation attenuates pain suppression by opioids and enhances the development of opioid tolerance and addiction, drug abuse, and other negative side effects such as respiratory depression and hyperalgesia. Drug candidates that target TLR4 may improve opioid-based pain management therapies.^[119]

Agonists

Apart from LPS and its derivatives, up to 30 natural TLR4 agonists with diverse chemical structures have been postulated. However, besides DAMPs, the others have not demonstrated to be direct activators of TLR4 and could therefore act as chaperones for TLR4 or as promoters of LPS internalization ^[120]^[121]^[122].

Antagonists

As of 2020, there were no specific TLR4 antagonists approved as drugs.^[123]

Amitriptyline^[124]
Cyclobenzaprine^[124]
Eritoran^[125]
Ketotifen^[124]
Imipramine^[124]
Mianserin^[124]
Ibudilast^[126]
Pinocembrin^[127]
Resatorvid^[128]
M62812
Naloxone^[129]
(+)-Naloxone ("unnatural" isomer, lacks opioid receptor affinity so selective for TLR4 inhibition)^[114]
Naltrexone^[129]
(+)-Naltrexone^[129]
LPS-RS^[129]
Propentofylline^{[citation needed]}
Pentoxifylline^[130] (and downregulate TLR4 expression^[131])
Tapentadol (mixed agonist/antagonist)
TLR4-IN-C34^[132]
Palmitoylethanolamide^[133]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000136869 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000039005 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b Vaure C, Liu Y (2014). "A comparative review of toll-like receptor 4 expression and functionality in different animal species". Frontiers in Immunology. 5: 316. doi:10.3389/fimmu.2014.00316. PMC 4090903. PMID 25071777.
^ Vaure C, Liu Y (2014). "A comparative review of toll-like receptor 4 expression and functionality in different animal species". Frontiers in Immunology. 5: 316. doi:10.3389/fimmu.2014.00316. PMC 4090903. PMID 25071777.
^ Mahnke K, Becher E, Ricciardi-Castagnoli P, Luger TA, Schwarz T, Grabbe S (1997). "CD14 is Expressed by Subsets of Murine Dendritic Cells and Upregulated by Lipopolysaccharide". In Ricciardi-Castagnoli P (ed.). Dendritic Cells in Fundamental and Clinical Immunology. Vol. 417. Boston, MA: Springer US. pp. 145–159. doi:10.1007/978-1-4757-9966-8_25. ISBN 978-1-4757-9968-2.
^ Sabroe I, Jones EC, Usher LR, Whyte MK, Dower SK (May 2002). "Toll-like receptor (TLR)2 and TLR4 in human peripheral blood granulocytes: a critical role for monocytes in leukocyte lipopolysaccharide responses". Journal of Immunology. 168 (9): 4701–4710. doi:10.4049/jimmunol.168.9.4701. PMID 11971020.
^ ^a ^b Yang H, Wang H, Ju Z, Ragab AA, Lundbäck P, Long W, et al. (January 2015). "MD-2 is required for disulfide HMGB1-dependent TLR4 signaling". The Journal of Experimental Medicine. 212 (1): 5–14. doi:10.1084/jem.20141318. PMC 4291531. PMID 25559892.
^ ^a ^b Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, et al. (November 2005). "Regulation of lung injury and repair by Toll-like receptors and hyaluronan". Nature Medicine. 11 (11): 1173–1179. doi:10.1038/nm1315. PMID 16244651.
^ ^a ^b Fang H, Ang B, Xu X, Huang X, Wu Y, Sun Y, et al. (March 2014). "TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells". Cellular & Molecular Immunology. 11 (2): 150–159. doi:10.1038/cmi.2013.59. PMC 4003380. PMID 24362470.
^ ^a ^b Hernandez C, Huebener P, Schwabe RF (November 2016). "Damage-associated molecular patterns in cancer: a double-edged sword". Oncogene. 35 (46): 5931–5941. doi:10.1038/onc.2016.104. PMC 5119456. PMID 27086930.
^ ^a ^b Jang GY, Lee JW, Kim YS, Lee SE, Han HD, Hong KJ, et al. (December 2020). "Interactions between tumor-derived proteins and Toll-like receptors". Experimental & Molecular Medicine. 52 (12): 1926–1935. doi:10.1038/s12276-020-00540-4. PMC 8080774. PMID 33299138.
^ Molteni M, Gemma S, Rossetti C (2016). "The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation". Mediators of Inflammation. 2016: 6978936. doi:10.1155/2016/6978936. ISSN 0962-9351. PMC 4887650. PMID 27293318.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Molteni M, Gemma S, Rossetti C (2016). "The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation". Mediators of Inflammation. 2016: 6978936. doi:10.1155/2016/6978936. ISSN 0962-9351. PMC 4887650. PMID 27293318.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Roh JS, Sohn DH (2018-08-13). "Damage-Associated Molecular Patterns in Inflammatory Diseases". Immune Network. 18 (4): e27. doi:10.4110/in.2018.18.e27. ISSN 1598-2629. PMC 6117512. PMID 30181915.
^ Jang GY, Lee JW, Kim YS, Lee SE, Han HD, Hong KJ, Kang TH, Park YM (2020-12). "Interactions between tumor-derived proteins and Toll-like receptors". Experimental & Molecular Medicine. 52 (12): 1926–1935. doi:10.1038/s12276-020-00540-4. ISSN 2092-6413. PMC 8080774. PMID 33299138. {{cite journal}}: Check date values in: |date= (help)
^ Tsukamoto H, Takeuchi S, Kubota K, Kobayashi Y, Kozakai S, Ukai I, Shichiku A, Okubo M, Numasaki M, Kanemitsu Y, Matsumoto Y, Nochi T, Watanabe K, Aso H, Tomioka Y (2018-06). "Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent Toll-like receptor 4 internalization and LPS-induced TBK1–IKKϵ–IRF3 axis activation". Journal of Biological Chemistry. 293 (26): 10186–10201. doi:10.1074/jbc.M117.796631. PMC 6028956. PMID 29760187. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
^ Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO (2009-04). "The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex". Nature. 458 (7242): 1191–1195. doi:10.1038/nature07830. ISSN 0028-0836. {{cite journal}}: Check date values in: |date= (help)
^ Park BS, Lee JO (2013-12-06). "Recognition of lipopolysaccharide pattern by TLR4 complexes". Experimental & Molecular Medicine. 45 (12): e66–e66. doi:10.1038/emm.2013.97. ISSN 2092-6413. PMC 3880462. PMID 24310172.{{cite journal}}: CS1 maint: PMC format (link)
^ Steimle A, Autenrieth IB, Frick JS (2016-08). "Structure and function: Lipid A modifications in commensals and pathogens". International journal of medical microbiology: IJMM. 306 (5): 290–301. doi:10.1016/j.ijmm.2016.03.001. ISSN 1618-0607. PMID 27009633. {{cite journal}}: Check date values in: |date= (help)
^ Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO (2009-04). "The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex". Nature. 458 (7242): 1191–1195. doi:10.1038/nature07830. ISSN 0028-0836. {{cite journal}}: Check date values in: |date= (help)
^ Kelley SL, Lukk T, Nair SK, Tapping RI (2013-02-01). "The Crystal Structure of Human Soluble CD14 Reveals a Bent Solenoid with a Hydrophobic Amino-Terminal Pocket". The Journal of Immunology. 190 (3): 1304–1311. doi:10.4049/jimmunol.1202446. ISSN 0022-1767. PMC 3552104. PMID 23264655.{{cite journal}}: CS1 maint: PMC format (link)
^ Muroi M, Tanamoto KI (2002-11). "The polysaccharide portion plays an indispensable role in Salmonella lipopolysaccharide-induced activation of NF-kappaB through human toll-like receptor 4". Infection and Immunity. 70 (11): 6043–6047. doi:10.1128/IAI.70.11.6043-6047.2002. ISSN 0019-9567. PMID 12379680. {{cite journal}}: Check date values in: |date= (help)
^ Cavaillon JM, Fitting C, Caroff M, Haeffner-Cavaillon N (1989-03). "Dissociation of cell-associated interleukin-1 (IL-1) and IL-1 release induced by lipopolysaccharide and lipid A". Infection and Immunity. 57 (3): 791–797. doi:10.1128/iai.57.3.791-797.1989. ISSN 0019-9567. PMC 313178. PMID 2537258. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
^ Shen H, Tesar BM, Walker WE, Goldstein DR (2008-08-01). "Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation". Journal of Immunology (Baltimore, Md.: 1950). 181 (3): 1849–1858. doi:10.4049/jimmunol.181.3.1849. ISSN 1550-6606. PMC 2507878. PMID 18641322.
^ Shen H, Tesar BM, Walker WE, Goldstein DR (2008-08-01). "Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation". Journal of Immunology (Baltimore, Md.: 1950). 181 (3): 1849–1858. doi:10.4049/jimmunol.181.3.1849. ISSN 1550-6606. PMC 2507878. PMID 18641322.
^ Lu YC, Yeh WC, Ohashi PS (May 2008). "LPS/TLR4 signal transduction pathway". Cytokine. 42 (2): 145–151. doi:10.1016/j.cyto.2008.01.006. PMID 18304834.
^ Pålsson-McDermott EM, O'Neill LA (October 2004). "Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4". Immunology. 113 (2): 153–162. doi:10.1111/j.1365-2567.2004.01976.x. PMC 1782563. PMID 15379975.
^ Meissner F, Scheltema RA, Mollenkopf HJ, Mann M (2013-04-26). "Direct Proteomic Quantification of the Secretome of Activated Immune Cells". Science. 340 (6131): 475–478. doi:10.1126/science.1232578. ISSN 0036-8075.
^ Kawai T, Takeuchi O, Fujita T, Inoue Ji, Mühlradt PF, Sato S, Hoshino K, Akira S (2001-11-15). "Lipopolysaccharide Stimulates the MyD88-Independent Pathway and Results in Activation of IFN-Regulatory Factor 3 and the Expression of a Subset of Lipopolysaccharide-Inducible Genes". The Journal of Immunology. 167 (10): 5887–5894. doi:10.4049/jimmunol.167.10.5887. ISSN 0022-1767.
^ Chanteux H, Guisset AC, Pilette C, Sibille Y (2007-10-04). "LPS induces IL-10 production by human alveolar macrophages via MAPKinases- and Sp1-dependent mechanisms". Respiratory Research. 8 (1): 71. doi:10.1186/1465-9921-8-71. ISSN 1465-993X. PMC 2080632. PMID 17916230.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
^ Ciesielska A, Matyjek M, Kwiatkowska K (2020-10-15). "TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling". Cellular and Molecular Life Sciences. 78 (4): 1233–1261. doi:10.1007/s00018-020-03656-y. ISSN 1420-682X.
^ Meissner F, Scheltema RA, Mollenkopf HJ, Mann M (2013-04-26). "Direct Proteomic Quantification of the Secretome of Activated Immune Cells". Science. 340 (6131): 475–478. doi:10.1126/science.1232578. ISSN 0036-8075.
^ Kawai T, Takeuchi O, Fujita T, Inoue Ji, Mühlradt PF, Sato S, Hoshino K, Akira S (2001-11-15). "Lipopolysaccharide Stimulates the MyD88-Independent Pathway and Results in Activation of IFN-Regulatory Factor 3 and the Expression of a Subset of Lipopolysaccharide-Inducible Genes". The Journal of Immunology. 167 (10): 5887–5894. doi:10.4049/jimmunol.167.10.5887. ISSN 0022-1767.
^ Chanteux H, Guisset AC, Pilette C, Sibille Y (2007-10-04). "LPS induces IL-10 production by human alveolar macrophages via MAPKinases- and Sp1-dependent mechanisms". Respiratory Research. 8 (1): 71. doi:10.1186/1465-9921-8-71. ISSN 1465-993X. PMC 2080632. PMID 17916230.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
^ O'Neill LA, Golenbock D, Bowie AG (June 2013). "The history of Toll-like receptors - redefining innate immunity". Nature Reviews. Immunology. 13 (6): 453–460. doi:10.1038/nri3446. hdl:2262/72552. PMID 23681101. S2CID 205491986.
^ Lien E, Means TK, Heine H, Yoshimura A, Kusumoto S, Fukase K, Fenton MJ, Oikawa M, Qureshi N, Monks B, Finberg RW, Ingalls RR, Golenbock DT (2000-02). "Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide". The Journal of Clinical Investigation. 105 (4): 497–504. doi:10.1172/JCI8541. ISSN 0021-9738. PMID 10683379. {{cite journal}}: Check date values in: |date= (help)
^ Shetab Boushehri MA, Lamprecht A (2018-11-05). "TLR4-Based Immunotherapeutics in Cancer: A Review of the Achievements and Shortcomings". Molecular Pharmaceutics. 15 (11): 4777–4800. doi:10.1021/acs.molpharmaceut.8b00691. ISSN 1543-8384.
^ Shetab Boushehri MA, Lamprecht A (2018-11-05). "TLR4-Based Immunotherapeutics in Cancer: A Review of the Achievements and Shortcomings". Molecular Pharmaceutics. 15 (11): 4777–4800. doi:10.1021/acs.molpharmaceut.8b00691. ISSN 1543-8384.
^ Shen H, Tesar BM, Walker WE, Goldstein DR (2008-08-01). "Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation". Journal of Immunology (Baltimore, Md.: 1950). 181 (3): 1849–1858. doi:10.4049/jimmunol.181.3.1849. ISSN 1550-6606. PMC 2507878. PMID 18641322.
^ Kaisho T, Takeuchi O, Kawai T, Hoshino K, Akira S (2001-05-01). "Endotoxin-induced maturation of MyD88-deficient dendritic cells". Journal of Immunology (Baltimore, Md.: 1950). 166 (9): 5688–5694. doi:10.4049/jimmunol.166.9.5688. ISSN 0022-1767. PMID 11313410.
^ Hoebe K, Janssen EM, Kim SO, Alexopoulou L, Flavell RA, Han J, Beutler B (2003-12). "Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways". Nature Immunology. 4 (12): 1223–1229. doi:10.1038/ni1010. ISSN 1529-2916. {{cite journal}}: Check date values in: |date= (help)
^ Shen H, Tesar BM, Walker WE, Goldstein DR (2008-08-01). "Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation". Journal of Immunology (Baltimore, Md.: 1950). 181 (3): 1849–1858. doi:10.4049/jimmunol.181.3.1849. ISSN 1550-6606. PMC 2507878. PMID 18641322.
^ Trombetta ES, Ebersold M, Garrett W, Pypaert M, Mellman I (2003-02-28). "Activation of Lysosomal Function During Dendritic Cell Maturation". Science. 299 (5611): 1400–1403. doi:10.1126/science.1080106. ISSN 0036-8075.
^ Turley SJ, Inaba K, Garrett WS, Ebersold M, Unternaehrer J, Steinman RM, Mellman I (2000-04-21). "Transport of Peptide-MHC Class II Complexes in Developing Dendritic Cells". Science. 288 (5465): 522–527. doi:10.1126/science.288.5465.522. ISSN 0036-8075.
^ Nair-Gupta P, Baccarini A, Tung N, Seyffer F, Florey O, Huang Y, Banerjee M, Overholtzer M, Roche PA, Tampé R, Brown BD, Amsen D, Whiteheart SW, Blander JM (2014-07). "TLR Signals Induce Phagosomal MHC-I Delivery from the Endosomal Recycling Compartment to Allow Cross-Presentation". Cell. 158 (3): 506–521. doi:10.1016/j.cell.2014.04.054. ISSN 0092-8674. PMC 4212008. PMID 25083866. {{cite journal}}: Check date values in: |date= (help); no-break space character in |first11= at position 6 (help); no-break space character in |first13= at position 7 (help); no-break space character in |first14= at position 3 (help); no-break space character in |first9= at position 5 (help)CS1 maint: PMC format (link)
^ Paavonen J, Jenkins D, Bosch FX, Naud P, Salmerón J, Wheeler CM, Chow SN, Apter DL, Kitchener HC, Castellsague X, de Carvalho NS, Skinner SR, Harper DM, Hedrick JA, Jaisamrarn U (2007-06-30). "Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial". Lancet (London, England). 369 (9580): 2161–2170. doi:10.1016/S0140-6736(07)60946-5. ISSN 1474-547X. PMID 17602732.
^ Kundi M (2007-04). "New hepatitis B vaccine formulated with an improved adjuvant system". Expert Review of Vaccines. 6 (2): 133–140. doi:10.1586/14760584.6.2.133. ISSN 1744-8395. PMID 17408363. {{cite journal}}: Check date values in: |date= (help)
^ Garçon N, Di Pasquale A (2017-01-02). "From discovery to licensure, the Adjuvant System story". Human Vaccines & Immunotherapeutics. 13 (1): 19–33. doi:10.1080/21645515.2016.1225635. ISSN 2164-5515. PMC 5287309. PMID 27636098.{{cite journal}}: CS1 maint: PMC format (link)
^ Beutler B, Rehli M (2002). "Evolution of the TIR, Tolls and TLRS: Functional Inferences from Computational Biology". Toll-Like Receptor Family Members and Their Ligands. Current Topics in Microbiology and Immunology. Vol. 270. pp. 1–21. doi:10.1007/978-3-642-59430-4_1. ISBN 978-3-642-63975-3. PMID 12467241.
^ Smirnova I, Poltorak A, Chan EK, McBride C, Beutler B (2000). "Phylogenetic variation and polymorphism at the toll-like receptor 4 locus (TLR4)". Genome Biology. 1 (1): RESEARCH002. doi:10.1186/gb-2000-1-1-research002. PMC 31919. PMID 11104518.
^ Quach H, Wilson D, Laval G, Patin E, Manry J, Guibert J, et al. (December 2013). "Different selective pressures shape the evolution of Toll-like receptors in human and African great ape populations". Human Molecular Genetics. 22 (23): 4829–4840. doi:10.1093/hmg/ddt335. PMC 3820138. PMID 23851028.
^ ^a ^b Barreiro LB, Ben-Ali M, Quach H, Laval G, Patin E, Pickrell JK, et al. (July 2009). "Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense". PLOS Genetics. 5 (7): e1000562. doi:10.1371/journal.pgen.1000562. PMC 2702086. PMID 19609346.
^ Plantinga TS, Ioana M, Alonso S, Izagirre N, Hervella M, Joosten LA, et al. (2012). "The evolutionary history of TLR4 polymorphisms in Europe". Journal of Innate Immunity. 4 (2): 168–175. doi:10.1159/000329492. PMC 6741577. PMID 21968286.
^ Noreen M, Shah MA, Mall SM, Choudhary S, Hussain T, Ahmed I, Jalil SF, Raza MI (2012-03). "TLR4 polymorphisms and disease susceptibility". Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.] 61 (3): 177–188. doi:10.1007/s00011-011-0427-1. ISSN 1420-908X. PMID 22277994. {{cite journal}}: Check date values in: |date= (help)
^ Long H, O'Connor BP, Zemans RL, Zhou X, Yang IV, Schwartz DA (2014-04-02). "The Toll-Like Receptor 4 Polymorphism Asp299Gly but Not Thr399Ile Influences TLR4 Signaling and Function". PLOS ONE. 9 (4): e93550. doi:10.1371/journal.pone.0093550. ISSN 1932-6203. PMC 3973565. PMID 24695807.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
^ journals.aai.org https://journals.aai.org/jimmunol/article/188/9/4506/39640. Retrieved 2024-02-20. {{cite web}}: Missing or empty |title= (help)
^ Ohto U, Yamakawa N, Akashi-Takamura S, Miyake K, Shimizu T (2012-11-23). "Structural Analyses of Human Toll-like Receptor 4 Polymorphisms D299G and T399I". The Journal of Biological Chemistry. 287 (48): 40611–40617. doi:10.1074/jbc.M112.404608. ISSN 0021-9258. PMC 3504774. PMID 23055527.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Akira S, Takeda K (2004-07). "Toll-like receptor signalling". Nature Reviews. Immunology. 4 (7): 499–511. doi:10.1038/nri1391. ISSN 1474-1733. PMID 15229469. {{cite journal}}: Check date values in: |date= (help)
^ Molteni M, Gemma S, Rossetti C (2016). "The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation". Mediators of Inflammation. 2016. doi:10.1155/2016/6978936. PMID 27293318.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Ciesielska A, Matyjek M, Kwiatkowska K (February 2021). "TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling". Cellular and Molecular Life Sciences. 78 (4): 1233–1261. doi:10.1007/s00018-020-03656-y. PMC 7904555. PMID 33057840.
^ Netea MG, Wijmenga C, O'Neill LA (2012-05-18). "Genetic variation in Toll-like receptors and disease susceptibility". Nature Immunology. 13 (6): 535–542. doi:10.1038/ni.2284. ISSN 1529-2916. PMID 22610250.
^ Chettab K, Fitzsimmons C, Novikov A, Denis M, Phelip C, Mathé D, Choffour PA, Beaumel S, Fourmaux E, Norca P, Kryza D, Evesque A, Jordheim LP, Perrial E, Matera EL (2023). "A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models". Frontiers in Immunology. 14: 1066402. doi:10.3389/fimmu.2023.1066402. ISSN 1664-3224. PMID 37223101.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Richert I, Berchard P, Abbes L, Novikov A, Chettab K, Vandermoeten A, Dumontet C, Karanian M, Kerzerho J, Caroff M, Blay JY, Dutour A (2023-09-19). "A TLR4 Agonist Induces Osteosarcoma Regression by Inducing an Antitumor Immune Response and Reprogramming M2 Macrophages to M1 Macrophages". Cancers. 15 (18): 4635. doi:10.3390/cancers15184635. ISSN 2072-6694. PMID 37760603.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Maruyama K, Selmani Z, Ishii H, Yamaguchi K (2011-03). "Innate immunity and cancer therapy". International Immunopharmacology. 11 (3): 350–357. doi:10.1016/j.intimp.2010.09.012. ISSN 1878-1705. PMID 20955832. {{cite journal}}: Check date values in: |date= (help)
^ Starnes CO (1992-05-07). "Coley's toxins in perspective". Nature. 357 (6373): 11–12. doi:10.1038/357011a0. ISSN 0028-0836. PMID 1574121.
^ Tsuji S, Matsumoto M, Takeuchi O, Akira S, Azuma I, Hayashi A, Toyoshima K, Seya T (2000-12). Kaufmann SH (ed.). "Maturation of Human Dendritic Cells by Cell Wall Skeleton of Mycobacterium bovis Bacillus Calmette-Guérin: Involvement of Toll-Like Receptors". Infection and Immunity. 68 (12): 6883–6890. doi:10.1128/IAI.68.12.6883-6890.2000. ISSN 0019-9567. PMC 97794. PMID 11083809. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
^ Ryoma Y, Moriya Y, Okamoto M, Kanaya I, Saito M, Sato M (2004-09-01). "Biological Effect of OK-432 (Picibanil) and Possible Application to Dendritic Cell Therapy". Anticancer Research. 24 (5C): 3295–3302. ISSN 0250-7005. PMID 15515424.
^ academic.oup.com https://academic.oup.com/jnci/article/95/4/316/2520610. Retrieved 2024-02-20. {{cite web}}: Missing or empty |title= (help)
^ academic.oup.com https://academic.oup.com/jnci/article-abstract/4/5/461/905560. Retrieved 2024-02-20. {{cite web}}: Missing or empty |title= (help)
^ Berendt MJ, North RJ, Kirstein DP (1978-12-01). "The immunological basis of endotoxin-induced tumor regression. Requirement for a pre-existing state of concomitant anti-tumor immunity". The Journal of Experimental Medicine. 148 (6): 1560–1569. doi:10.1084/jem.148.6.1560. ISSN 0022-1007. PMC 2185097. PMID 309922.
^ Engelhardt R, Mackensen A, Galanos C (1991-05-15). "Phase I trial of intravenously administered endotoxin (Salmonella abortus equi) in cancer patients". Cancer Research. 51 (10): 2524–2530. ISSN 0008-5472. PMID 2021932.
^ "Melacine - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2024-02-20.
^ Bhatia S, Miller NJ, Lu H, Longino NV, Ibrani D, Shinohara MM, Byrd DR, Parvathaneni U, Kulikauskas R, Ter Meulen J, Hsu FJ, Koelle DM, Nghiem P (2019-02-15). "Intratumoral G100, a TLR4 Agonist, Induces Antitumor Immune Responses and Tumor Regression in Patients with Merkel Cell Carcinoma". Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 25 (4): 1185–1195. doi:10.1158/1078-0432.CCR-18-0469. ISSN 1557-3265. PMC 6368904. PMID 30093453.
^ Halwani AS, Panizo C, Isufi I, Herrera AF, Okada CY, Cull EH, Kis B, Chaves JM, Bartlett NL, Ai W, de la Cruz-Merino L, Bryan LJ, Houot R, Linton K, Briones J (2022-04). "Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma". Leukemia & Lymphoma. 63 (4): 821–833. doi:10.1080/10428194.2021.2010057. ISSN 1029-2403. PMID 34865586. {{cite journal}}: Check date values in: |date= (help)
^ Flowers C, Panizo C, Isufi I, Herrera AF, Okada C, Cull EH, Kis B, Chaves JM, Bartlett NL, Ai W, de la Cruz-Merino L, Bryan LJ, Houot R, Linton K, Briones J (2017-12-08). "Intratumoral G100 Induces Systemic Immunity and Abscopal Tumor Regression in Patients with Follicular Lymphoma: Results of a Phase 1/ 2 Study Examining G100 Alone and in Combination with Pembrolizumab". Blood. 130: 2771. doi:10.1182/blood.V130.Suppl_1.2771.2771. ISSN 0006-4971.
^ Rajput S, Volk-Draper LD, Ran S (2013-08). "TLR4 is a novel determinant of the response to paclitaxel in breast cancer". Molecular Cancer Therapeutics. 12 (8): 1676–1687. doi:10.1158/1535-7163.MCT-12-1019. ISSN 1538-8514. PMC 3742631. PMID 23720768. {{cite journal}}: Check date values in: |date= (help)
^ Flowers C, Panizo C, Isufi I, Herrera AF, Okada C, Cull EH, Kis B, Chaves JM, Bartlett NL, Ai W, de la Cruz-Merino L, Bryan LJ, Houot R, Linton K, Briones J (2017-12-08). "Intratumoral G100 Induces Systemic Immunity and Abscopal Tumor Regression in Patients with Follicular Lymphoma: Results of a Phase 1/ 2 Study Examining G100 Alone and in Combination with Pembrolizumab". Blood. 130: 2771. doi:10.1182/blood.V130.Suppl_1.2771.2771. ISSN 0006-4971.
^ Zhang R, Zhao J, Xu J, Jiao DX, Wang J, Gong ZQ, Jia JH (2017-10). "Andrographolide suppresses proliferation of human colon cancer SW620 cells through the TLR4/NF-κB/MMP-9 signaling pathway". Oncology Letters. 14 (4): 4305–4310. doi:10.3892/ol.2017.6669. ISSN 1792-1074. PMC 5604146. PMID 28943944. {{cite journal}}: Check date values in: |date= (help)
^ Wang CH, Wang PJ, Hsieh YC, Lo S, Lee YC, Chen YC, Tsai CH, Chiu WC, Chu-Sung Hu S, Lu CW, Yang YF, Chiu CC, Ou-Yang F, Wang YM, Hou MF (2018-02-01). "Resistin facilitates breast cancer progression via TLR4-mediated induction of mesenchymal phenotypes and stemness properties". Oncogene. 37 (5): 589–600. doi:10.1038/onc.2017.357. ISSN 1476-5594. PMID 28991224.
^ Kelly MG, Alvero AB, Chen R, Silasi DA, Abrahams VM, Chan S, Visintin I, Rutherford T, Mor G (2006-04-01). "TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer". Cancer Research. 66 (7): 3859–3868. doi:10.1158/0008-5472.CAN-05-3948. ISSN 0008-5472. PMID 16585214.
^ Jang GY, Lee JW, Kim YS, Lee SE, Han HD, Hong KJ, Kang TH, Park YM (2020-12). "Interactions between tumor-derived proteins and Toll-like receptors". Experimental & Molecular Medicine. 52 (12): 1926–1935. doi:10.1038/s12276-020-00540-4. ISSN 2092-6413. PMC 8080774. PMID 33299138. {{cite journal}}: Check date values in: |date= (help)
^ Khademalhosseini M, Arababadi MK (2019-05-01). "Toll-like receptor 4 and breast cancer: an updated systematic review". Breast Cancer. 26 (3): 265–271. doi:10.1007/s12282-018-00935-2. ISSN 1880-4233.
^ Roh JS, Sohn DH (2018-08). "Damage-Associated Molecular Patterns in Inflammatory Diseases". Immune Network. 18 (4): e27. doi:10.4110/in.2018.18.e27. ISSN 1598-2629. PMC 6117512. PMID 30181915. {{cite journal}}: Check date values in: |date= (help)
^ Jang GY, Lee JW, Kim YS, Lee SE, Han HD, Hong KJ, Kang TH, Park YM (2020-12). "Interactions between tumor-derived proteins and Toll-like receptors". Experimental & Molecular Medicine. 52 (12): 1926–1935. doi:10.1038/s12276-020-00540-4. ISSN 2092-6413. PMC 8080774. PMID 33299138. {{cite journal}}: Check date values in: |date= (help)
^ Hernandez C, Huebener P, Schwabe RF (2016-11-17). "Damage-associated molecular patterns in cancer: a double-edged sword". Oncogene. 35 (46): 5931–5941. doi:10.1038/onc.2016.104. ISSN 1476-5594. PMC 5119456. PMID 27086930.
^ Zhu L, Yuan H, Jiang T, Wang R, Ma H, Zhang S (2013-12-20). "Association of TLR2 and TLR4 Polymorphisms with Risk of Cancer: A Meta-Analysis". PLoS ONE. 8 (12): e82858. doi:10.1371/journal.pone.0082858. ISSN 1932-6203. PMC 3869723. PMID 24376595.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Vaure C, Liu Y (2014). "A Comparative Review of Toll-Like Receptor 4 Expression and Functionality in Different Animal Species". Frontiers in Immunology. 5. doi:10.3389/fimmu.2014.00316/full. ISSN 1664-3224.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Wardill HR, Van Sebille YZ, Mander KA, Gibson RJ, Logan RM, Bowen JM, Sonis ST (2015-02). "Toll-like receptor 4 signaling: a common biological mechanism of regimen-related toxicities: an emerging hypothesis for neuropathy and gastrointestinal toxicity". Cancer Treatment Reviews. 41 (2): 122–128. doi:10.1016/j.ctrv.2014.11.005. ISSN 1532-1967. PMID 25512119. {{cite journal}}: Check date values in: |date= (help)
^ Molteni M, Gemma S, Rossetti C (2016). "The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation". Mediators of Inflammation. 2016: 6978936. doi:10.1155/2016/6978936. ISSN 1466-1861. PMC 4887650. PMID 27293318.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Tahara K, Kim HD, Jin JJ, Maxwell JA, Li L, Fukuchi Ki (2006-11). "Role of toll-like receptor signalling in Abeta uptake and clearance". Brain: A Journal of Neurology. 129 (Pt 11): 3006–3019. doi:10.1093/brain/awl249. ISSN 1460-2156. PMC 2445613. PMID 16984903. {{cite journal}}: Check date values in: |date= (help)
^ Buchanan MM, Hutchinson M, Watkins LR, Yin H (2010-7). "Toll-like Receptor 4 in CNS Pathologies". Journal of neurochemistry. 114 (1): 13–27. doi:10.1111/j.1471-4159.2010.06736.x. ISSN 0022-3042. PMC 2909662. PMID 20402965. {{cite journal}}: Check date values in: |date= (help)
^ Qin Y, Liu Y, Hao W, Decker Y, Tomic I, Menger MD, Liu C, Fassbender K (2016-10-15). "Stimulation of TLR4 Attenuates Alzheimer's Disease-Related Symptoms and Pathology in Tau-Transgenic Mice". Journal of Immunology (Baltimore, Md.: 1950). 197 (8): 3281–3292. doi:10.4049/jimmunol.1600873. ISSN 1550-6606. PMID 27605009.
^ Gambuzza M, Licata N, Palella E, Celi D, Foti Cuzzola V, Italiano D, Marino S, Bramanti P (2011-10-28). "Targeting Toll-like receptors: emerging therapeutics for multiple sclerosis management". Journal of Neuroimmunology. 239 (1–2): 1–12. doi:10.1016/j.jneuroim.2011.08.010. ISSN 1872-8421. PMID 21889214.
^ Buchanan MM, Hutchinson M, Watkins LR, Yin H (2010-7). "Toll-like Receptor 4 in CNS Pathologies". Journal of neurochemistry. 114 (1): 13–27. doi:10.1111/j.1471-4159.2010.06736.x. ISSN 0022-3042. PMC 2909662. PMID 20402965. {{cite journal}}: Check date values in: |date= (help)
^ Rannikko EH, Weber SS, Kahle PJ (2015-09-07). "Exogenous α-synuclein induces toll-like receptor 4 dependent inflammatory responses in astrocytes". BMC neuroscience. 16: 57. doi:10.1186/s12868-015-0192-0. ISSN 1471-2202. PMC 4562100. PMID 26346361.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, Bode B, Manietta N, Walter J, Schulz-Schuffer W, Fassbender K (2007). "Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease". Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology. 20 (6): 947–956. doi:10.1159/000110455. ISSN 1015-8987. PMID 17982277.
^ Land WG (2015-02). "The Role of Damage-Associated Molecular Patterns in Human Diseases: Part I - Promoting inflammation and immunity". Sultan Qaboos University Medical Journal. 15 (1): e9–e21. ISSN 2075-051X. PMC 4318613. PMID 25685392. {{cite journal}}: Check date values in: |date= (help)
^ Festoff BW, Sajja RK, van Dreden P, Cucullo L (2016-08-24). "HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer's disease". Journal of Neuroinflammation. 13 (1): 194. doi:10.1186/s12974-016-0670-z. ISSN 1742-2094. PMC 4995775. PMID 27553758.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Chaves ML, Camozzato AL, Ferreira ED, Piazenski I, Kochhann R, Dall'Igna O, Mazzini GS, Souza DO, Portela LV (2010-01-27). "Serum levels of S100B and NSE proteins in Alzheimer's disease patients". Journal of Neuroinflammation. 7: 6. doi:10.1186/1742-2094-7-6. ISSN 1742-2094. PMC 2832635. PMID 20105309.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Yang Y, Han C, Guo L, Guan Q (2018-04). "High expression of the HMGB1-TLR4 axis and its downstream signaling factors in patients with Parkinson's disease and the relationship of pathological staging". Brain and Behavior. 8 (4): e00948. doi:10.1002/brb3.948. ISSN 2162-3279. PMC 5893335. PMID 29670828. {{cite journal}}: Check date values in: |date= (help)
^ Wu L, Xian X, Xu G, Tan Z, Dong F, Zhang M, Zhang F (2022-08-21). "Toll-Like Receptor 4: A Promising Therapeutic Target for Alzheimer's Disease". Mediators of Inflammation. 2022: 1–20. doi:10.1155/2022/7924199. ISSN 1466-1861.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Leitner GR, Wenzel TJ, Marshall N, Gates EJ, Klegeris A (2019-10). "Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders". Expert Opinion on Therapeutic Targets. 23 (10): 865–882. doi:10.1080/14728222.2019.1676416. ISSN 1744-7631. PMID 31580163. {{cite journal}}: Check date values in: |date= (help)
^ Michaud JP, Hallé M, Lampron A, Thériault P, Préfontaine P, Filali M, Tribout-Jover P, Lanteigne AM, Jodoin R, Cluff C, Brichard V, Palmantier R, Pilorget A, Larocque D, Rivest S (2013-01-29). "Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer's disease-related pathology". Proceedings of the National Academy of Sciences of the United States of America. 110 (5): 1941–1946. doi:10.1073/pnas.1215165110. ISSN 1091-6490. PMC 3562771. PMID 23322736.
^ Leitner GR, Wenzel TJ, Marshall N, Gates EJ, Klegeris A (2019-10). "Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders". Expert Opinion on Therapeutic Targets. 23 (10): 865–882. doi:10.1080/14728222.2019.1676416. ISSN 1744-7631. PMID 31580163. {{cite journal}}: Check date values in: |date= (help)
^ Shavit Y, Wolf G, Goshen I, Livshits D, Yirmiya R (May 2005). "Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance". Pain. 115 (1–2): 50–59. doi:10.1016/j.pain.2005.02.003. PMID 15836969. S2CID 7286123.
^ Mohan S, Davis RL, DeSilva U, Stevens CW (October 2010). "Dual regulation of mu opioid receptors in SK-N-SH neuroblastoma cells by morphine and interleukin-1β: evidence for opioid-immune crosstalk". Journal of Neuroimmunology. 227 (1–2): 26–34. doi:10.1016/j.jneuroim.2010.06.007. PMC 2942958. PMID 20615556.
^ Komatsu T, Sakurada S, Katsuyama S, Sanai K, Sakurada T (2009). Mechanism of allodynia evoked by intrathecal morphine-3-glucuronide in mice. International Review of Neurobiology. Vol. 85. pp. 207–19. doi:10.1016/S0074-7742(09)85016-2. ISBN 978-0-12-374893-5. PMID 19607972.
^ Lewis SS, Hutchinson MR, Rezvani N, Loram LC, Zhang Y, Maier SF, et al. (January 2010). "Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta". Neuroscience. 165 (2): 569–583. doi:10.1016/j.neuroscience.2009.10.011. PMC 2795035. PMID 19833175.
^ Shen CH, Tsai RY, Shih MS, Lin SL, Tai YH, Chien CC, Wong CS (February 2011). "Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats". Anesthesia and Analgesia. 112 (2): 454–459. doi:10.1213/ANE.0b013e3182025b15. PMID 21081778. S2CID 12295407.
^ Hook MA, Washburn SN, Moreno G, Woller SA, Puga D, Lee KH, Grau JW (February 2011). "An IL-1 receptor antagonist blocks a morphine-induced attenuation of locomotor recovery after spinal cord injury". Brain, Behavior, and Immunity. 25 (2): 349–359. doi:10.1016/j.bbi.2010.10.018. PMC 3025088. PMID 20974246.
^ Watkins LR, Hutchinson MR, Rice KC, Maier SF (November 2009). "The "toll" of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia". Trends in Pharmacological Sciences. 30 (11): 581–591. doi:10.1016/j.tips.2009.08.002. PMC 2783351. PMID 19762094.
^ ^a ^b ^c Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, et al. (July 2008). "Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4)". The European Journal of Neuroscience. 28 (1): 20–29. doi:10.1111/j.1460-9568.2008.06321.x. PMC 2588470. PMID 18662331.
^ Hutchinson MR, Coats BD, Lewis SS, Zhang Y, Sprunger DB, Rezvani N, et al. (November 2008). "Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia". Brain, Behavior, and Immunity. 22 (8): 1178–1189. doi:10.1016/j.bbi.2008.05.004. PMC 2783238. PMID 18599265.
^ Hutchinson MR, Lewis SS, Coats BD, Rezvani N, Zhang Y, Wieseler JL, et al. (May 2010). "Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences". Neuroscience. 167 (3): 880–893. doi:10.1016/j.neuroscience.2010.02.011. PMC 2854318. PMID 20178837.
^ Lin SL, Tsai RY, Tai YH, Cherng CH, Wu CT, Yeh CC, Wong CS (February 2010). "Ultra-low dose naloxone upregulates interleukin-10 expression and suppresses neuroinflammation in morphine-tolerant rat spinal cords". Behavioural Brain Research. 207 (1): 30–36. doi:10.1016/j.bbr.2009.09.034. PMID 19799935. S2CID 5128970.
^ "Neuroscience: Making morphine work better". Nature. 484 (7395): 419. 26 April 2012. Bibcode:2012Natur.484Q.419.. doi:10.1038/484419a. S2CID 52805136.
^ Drahl C (22 August 2012). "Small Molecules Target Toll-Like Receptors". Chemical & Engineering News.
^ Yang H, Wang H, Ju Z, Ragab AA, Lundbäck P, Long W, Valdes-Ferrer SI, He M, Pribis JP, Li J, Lu B, Gero D, Szabo C, Antoine DJ, Harris HE (2015-01-05). "MD-2 is required for disulfide HMGB1–dependent TLR4 signaling". Journal of Experimental Medicine. 212 (1): 5–14. doi:10.1084/jem.20141318. ISSN 1540-9538. PMC 4291531. PMID 25559892.{{cite journal}}: CS1 maint: PMC format (link)
^ Manček‐Keber Mateja, Jerala R (2015-02). "Postulates for validating TLR4 agonists". European Journal of Immunology. 45 (2): 356–370. doi:10.1002/eji.201444462. ISSN 0014-2980. {{cite journal}}: Check date values in: |date= (help); Vancouver style error: non-Latin character in name 1 (help)
^ Kim HM, Kim YM (2018-10). "HMGB1: LPS Delivery Vehicle for Caspase-11-Mediated Pyroptosis". Immunity. 49 (4): 582–584. doi:10.1016/j.immuni.2018.09.021. {{cite journal}}: Check date values in: |date= (help)
^ Romerio A, Peri F (2020). "Increasing the Chemical Variety of Small-Molecule-Based TLR4 Modulators: An Overview". Frontiers in Immunology. 11: 1210. doi:10.3389/fimmu.2020.01210. PMC 7381287. PMID 32765484.
^ ^a ^b ^c ^d ^e Hutchinson MR, Loram LC, Zhang Y, Shridhar M, Rezvani N, Berkelhammer D, et al. (June 2010). "Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity". Neuroscience. 168 (2): 551–563. doi:10.1016/j.neuroscience.2010.03.067. PMC 2872682. PMID 20381591.
^ Chen F, Zou L, Williams B, Chao W (November 2021). "Targeting Toll-Like Receptors in Sepsis: From Bench to Clinical Trials". Antioxidants & Redox Signaling. 35 (15): 1324–1339. doi:10.1089/ars.2021.0005. PMC 8817700. PMID 33588628.
^ Jia ZJ, Wu FX, Huang QH, Liu JM (April 2012). "[Toll-like receptor 4: the potential therapeutic target for neuropathic pain]". Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae. 34 (2): 168–173. doi:10.3881/j.issn.1000-503X.2012.02.013. PMID 22776604.
^ Lan X, Han X, Li Q, Li Q, Gao Y, Cheng T, et al. (March 2017). "Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia". Brain, Behavior, and Immunity. 61: 326–339. doi:10.1016/j.bbi.2016.12.012. PMC 5453178. PMID 28007523.
^ Kaieda A, Takahashi M, Fukuda H, Okamoto R, Morimoto S, Gotoh M, et al. (December 2019). "Structure-Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]Pyridin-2-one-Based p38 MAP Kinase Inhibitors: Part 2". ChemMedChem. 14 (24): 2093–2101. doi:10.1002/cmdc.201900373. PMID 31697454. S2CID 207951964.
^ ^a ^b ^c ^d Hutchinson MR, Zhang Y, Shridhar M, Evans JH, Buchanan MM, Zhao TX, et al. (January 2010). "Evidence that opioids may have toll-like receptor 4 and MD-2 effects". Brain, Behavior, and Immunity. 24 (1): 83–95. doi:10.1016/j.bbi.2009.08.004. PMC 2788078. PMID 19679181.
^ Speer EM, Dowling DJ, Ozog LS, Xu J, Yang J, Kennady G, Levy O (May 2017). "Pentoxifylline inhibits TLR- and inflammasome-mediated in vitro inflammatory cytokine production in human blood with greater efficacy and potency in newborns". Pediatric Research. 81 (5): 806–816. doi:10.1038/pr.2017.6. PMID 28072760. S2CID 47210724.
^ Schüller SS, Wisgrill L, Herndl E, Spittler A, Förster-Waldl E, Sadeghi K, et al. (August 2017). "Pentoxifylline modulates LPS-induced hyperinflammation in monocytes of preterm infants in vitro". Pediatric Research. 82 (2): 215–225. doi:10.1038/pr.2017.41. PMID 28288151. S2CID 24897100.
^ Neal MD, Jia H, Eyer B, Good M, Guerriero CJ, Sodhi CP, et al. (2013). "Discovery and validation of a new class of small molecule Toll-like receptor 4 (TLR4) inhibitors". PLOS ONE. 8 (6): e65779. Bibcode:2013PLoSO...865779N. doi:10.1371/journal.pone.0065779. PMC 3680486. PMID 23776545.
^ Impellizzeri D, Campolo M, Di Paola R, Bruschetta G, de Stefano D, Esposito E, Cuzzocrea S (2015). "Ultramicronized palmitoylethanolamide reduces inflammation an a Th1-mediated model of colitis". European Journal of Inflammation. 13: 14–31. doi:10.1177/1721727X15575869. S2CID 79398556.

External links

Toll-Like+Receptor+4 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Overview of all the structural information available in the PDB for UniProt: O00206 (Toll-like receptor 4) at the PDBe-KB.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000136869 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000039005 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid25071777-5] Vaure C, Liu Y (2014). "A comparative review of toll-like receptor 4 expression and functionality in different animal species". Frontiers in Immunology. 5: 316. doi:10.3389/fimmu.2014.00316. PMC 4090903. PMID 25071777.

[6] Vaure C, Liu Y (2014). "A comparative review of toll-like receptor 4 expression and functionality in different animal species". Frontiers in Immunology. 5: 316. doi:10.3389/fimmu.2014.00316. PMC 4090903. PMID 25071777.

[7] Mahnke K, Becher E, Ricciardi-Castagnoli P, Luger TA, Schwarz T, Grabbe S (1997). "CD14 is Expressed by Subsets of Murine Dendritic Cells and Upregulated by Lipopolysaccharide". In Ricciardi-Castagnoli P (ed.). Dendritic Cells in Fundamental and Clinical Immunology. Vol. 417. Boston, MA: Springer US. pp. 145–159. doi:10.1007/978-1-4757-9966-8_25. ISBN 978-1-4757-9968-2.

[8] Sabroe I, Jones EC, Usher LR, Whyte MK, Dower SK (May 2002). "Toll-like receptor (TLR)2 and TLR4 in human peripheral blood granulocytes: a critical role for monocytes in leukocyte lipopolysaccharide responses". Journal of Immunology. 168 (9): 4701–4710. doi:10.4049/jimmunol.168.9.4701. PMID 11971020.

[pmid25559892-9] Yang H, Wang H, Ju Z, Ragab AA, Lundbäck P, Long W, et al. (January 2015). "MD-2 is required for disulfide HMGB1-dependent TLR4 signaling". The Journal of Experimental Medicine. 212 (1): 5–14. doi:10.1084/jem.20141318. PMC 4291531. PMID 25559892.

[:0-10] Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, et al. (November 2005). "Regulation of lung injury and repair by Toll-like receptors and hyaluronan". Nature Medicine. 11 (11): 1173–1179. doi:10.1038/nm1315. PMID 16244651.

[:1-11] Fang H, Ang B, Xu X, Huang X, Wu Y, Sun Y, et al. (March 2014). "TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells". Cellular & Molecular Immunology. 11 (2): 150–159. doi:10.1038/cmi.2013.59. PMC 4003380. PMID 24362470.

[:2-12] Hernandez C, Huebener P, Schwabe RF (November 2016). "Damage-associated molecular patterns in cancer: a double-edged sword". Oncogene. 35 (46): 5931–5941. doi:10.1038/onc.2016.104. PMC 5119456. PMID 27086930.

[:3-13] Jang GY, Lee JW, Kim YS, Lee SE, Han HD, Hong KJ, et al. (December 2020). "Interactions between tumor-derived proteins and Toll-like receptors". Experimental & Molecular Medicine. 52 (12): 1926–1935. doi:10.1038/s12276-020-00540-4. PMC 8080774. PMID 33299138.

[14] Molteni M, Gemma S, Rossetti C (2016). "The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation". Mediators of Inflammation. 2016: 6978936. doi:10.1155/2016/6978936. ISSN 0962-9351. PMC 4887650. PMID 27293318.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[15] Molteni M, Gemma S, Rossetti C (2016). "The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation". Mediators of Inflammation. 2016: 6978936. doi:10.1155/2016/6978936. ISSN 0962-9351. PMC 4887650. PMID 27293318.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[16] Roh JS, Sohn DH (2018-08-13). "Damage-Associated Molecular Patterns in Inflammatory Diseases". Immune Network. 18 (4): e27. doi:10.4110/in.2018.18.e27. ISSN 1598-2629. PMC 6117512. PMID 30181915.

[17] Jang GY, Lee JW, Kim YS, Lee SE, Han HD, Hong KJ, Kang TH, Park YM (2020-12). "Interactions between tumor-derived proteins and Toll-like receptors". Experimental & Molecular Medicine. 52 (12): 1926–1935. doi:10.1038/s12276-020-00540-4. ISSN 2092-6413. PMC 8080774. PMID 33299138. {{cite journal}}: Check date values in: |date= (help)

[18] Tsukamoto H, Takeuchi S, Kubota K, Kobayashi Y, Kozakai S, Ukai I, Shichiku A, Okubo M, Numasaki M, Kanemitsu Y, Matsumoto Y, Nochi T, Watanabe K, Aso H, Tomioka Y (2018-06). "Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent Toll-like receptor 4 internalization and LPS-induced TBK1–IKKϵ–IRF3 axis activation". Journal of Biological Chemistry. 293 (26): 10186–10201. doi:10.1074/jbc.M117.796631. PMC 6028956. PMID 29760187. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[19] Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO (2009-04). "The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex". Nature. 458 (7242): 1191–1195. doi:10.1038/nature07830. ISSN 0028-0836. {{cite journal}}: Check date values in: |date= (help)

[20] Park BS, Lee JO (2013-12-06). "Recognition of lipopolysaccharide pattern by TLR4 complexes". Experimental & Molecular Medicine. 45 (12): e66–e66. doi:10.1038/emm.2013.97. ISSN 2092-6413. PMC 3880462. PMID 24310172.{{cite journal}}: CS1 maint: PMC format (link)

[21] Steimle A, Autenrieth IB, Frick JS (2016-08). "Structure and function: Lipid A modifications in commensals and pathogens". International journal of medical microbiology: IJMM. 306 (5): 290–301. doi:10.1016/j.ijmm.2016.03.001. ISSN 1618-0607. PMID 27009633. {{cite journal}}: Check date values in: |date= (help)

[22] Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO (2009-04). "The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex". Nature. 458 (7242): 1191–1195. doi:10.1038/nature07830. ISSN 0028-0836. {{cite journal}}: Check date values in: |date= (help)

[23] Kelley SL, Lukk T, Nair SK, Tapping RI (2013-02-01). "The Crystal Structure of Human Soluble CD14 Reveals a Bent Solenoid with a Hydrophobic Amino-Terminal Pocket". The Journal of Immunology. 190 (3): 1304–1311. doi:10.4049/jimmunol.1202446. ISSN 0022-1767. PMC 3552104. PMID 23264655.{{cite journal}}: CS1 maint: PMC format (link)

[24] Muroi M, Tanamoto KI (2002-11). "The polysaccharide portion plays an indispensable role in Salmonella lipopolysaccharide-induced activation of NF-kappaB through human toll-like receptor 4". Infection and Immunity. 70 (11): 6043–6047. doi:10.1128/IAI.70.11.6043-6047.2002. ISSN 0019-9567. PMID 12379680. {{cite journal}}: Check date values in: |date= (help)

[25] Cavaillon JM, Fitting C, Caroff M, Haeffner-Cavaillon N (1989-03). "Dissociation of cell-associated interleukin-1 (IL-1) and IL-1 release induced by lipopolysaccharide and lipid A". Infection and Immunity. 57 (3): 791–797. doi:10.1128/iai.57.3.791-797.1989. ISSN 0019-9567. PMC 313178. PMID 2537258. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)

[26] Shen H, Tesar BM, Walker WE, Goldstein DR (2008-08-01). "Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation". Journal of Immunology (Baltimore, Md.: 1950). 181 (3): 1849–1858. doi:10.4049/jimmunol.181.3.1849. ISSN 1550-6606. PMC 2507878. PMID 18641322.

[27] Shen H, Tesar BM, Walker WE, Goldstein DR (2008-08-01). "Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation". Journal of Immunology (Baltimore, Md.: 1950). 181 (3): 1849–1858. doi:10.4049/jimmunol.181.3.1849. ISSN 1550-6606. PMC 2507878. PMID 18641322.

[Lu_2008-28] Lu YC, Yeh WC, Ohashi PS (May 2008). "LPS/TLR4 signal transduction pathway". Cytokine. 42 (2): 145–151. doi:10.1016/j.cyto.2008.01.006. PMID 18304834.

[Pålsson-McDermott_2004-29] Pålsson-McDermott EM, O'Neill LA (October 2004). "Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4". Immunology. 113 (2): 153–162. doi:10.1111/j.1365-2567.2004.01976.x. PMC 1782563. PMID 15379975.

[30] Meissner F, Scheltema RA, Mollenkopf HJ, Mann M (2013-04-26). "Direct Proteomic Quantification of the Secretome of Activated Immune Cells". Science. 340 (6131): 475–478. doi:10.1126/science.1232578. ISSN 0036-8075.

[31] Kawai T, Takeuchi O, Fujita T, Inoue Ji, Mühlradt PF, Sato S, Hoshino K, Akira S (2001-11-15). "Lipopolysaccharide Stimulates the MyD88-Independent Pathway and Results in Activation of IFN-Regulatory Factor 3 and the Expression of a Subset of Lipopolysaccharide-Inducible Genes". The Journal of Immunology. 167 (10): 5887–5894. doi:10.4049/jimmunol.167.10.5887. ISSN 0022-1767.

[32] Chanteux H, Guisset AC, Pilette C, Sibille Y (2007-10-04). "LPS induces IL-10 production by human alveolar macrophages via MAPKinases- and Sp1-dependent mechanisms". Respiratory Research. 8 (1): 71. doi:10.1186/1465-9921-8-71. ISSN 1465-993X. PMC 2080632. PMID 17916230.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[33] Ciesielska A, Matyjek M, Kwiatkowska K (2020-10-15). "TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling". Cellular and Molecular Life Sciences. 78 (4): 1233–1261. doi:10.1007/s00018-020-03656-y. ISSN 1420-682X.

[34] Meissner F, Scheltema RA, Mollenkopf HJ, Mann M (2013-04-26). "Direct Proteomic Quantification of the Secretome of Activated Immune Cells". Science. 340 (6131): 475–478. doi:10.1126/science.1232578. ISSN 0036-8075.

[35] Kawai T, Takeuchi O, Fujita T, Inoue Ji, Mühlradt PF, Sato S, Hoshino K, Akira S (2001-11-15). "Lipopolysaccharide Stimulates the MyD88-Independent Pathway and Results in Activation of IFN-Regulatory Factor 3 and the Expression of a Subset of Lipopolysaccharide-Inducible Genes". The Journal of Immunology. 167 (10): 5887–5894. doi:10.4049/jimmunol.167.10.5887. ISSN 0022-1767.

[36] Chanteux H, Guisset AC, Pilette C, Sibille Y (2007-10-04). "LPS induces IL-10 production by human alveolar macrophages via MAPKinases- and Sp1-dependent mechanisms". Respiratory Research. 8 (1): 71. doi:10.1186/1465-9921-8-71. ISSN 1465-993X. PMC 2080632. PMID 17916230.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[O'Neill_2013-37] O'Neill LA, Golenbock D, Bowie AG (June 2013). "The history of Toll-like receptors - redefining innate immunity". Nature Reviews. Immunology. 13 (6): 453–460. doi:10.1038/nri3446. hdl:2262/72552. PMID 23681101. S2CID 205491986.

[38] Lien E, Means TK, Heine H, Yoshimura A, Kusumoto S, Fukase K, Fenton MJ, Oikawa M, Qureshi N, Monks B, Finberg RW, Ingalls RR, Golenbock DT (2000-02). "Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide". The Journal of Clinical Investigation. 105 (4): 497–504. doi:10.1172/JCI8541. ISSN 0021-9738. PMID 10683379. {{cite journal}}: Check date values in: |date= (help)

[39] Shetab Boushehri MA, Lamprecht A (2018-11-05). "TLR4-Based Immunotherapeutics in Cancer: A Review of the Achievements and Shortcomings". Molecular Pharmaceutics. 15 (11): 4777–4800. doi:10.1021/acs.molpharmaceut.8b00691. ISSN 1543-8384.

[40] Shetab Boushehri MA, Lamprecht A (2018-11-05). "TLR4-Based Immunotherapeutics in Cancer: A Review of the Achievements and Shortcomings". Molecular Pharmaceutics. 15 (11): 4777–4800. doi:10.1021/acs.molpharmaceut.8b00691. ISSN 1543-8384.

[41] Shen H, Tesar BM, Walker WE, Goldstein DR (2008-08-01). "Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation". Journal of Immunology (Baltimore, Md.: 1950). 181 (3): 1849–1858. doi:10.4049/jimmunol.181.3.1849. ISSN 1550-6606. PMC 2507878. PMID 18641322.

[42] Kaisho T, Takeuchi O, Kawai T, Hoshino K, Akira S (2001-05-01). "Endotoxin-induced maturation of MyD88-deficient dendritic cells". Journal of Immunology (Baltimore, Md.: 1950). 166 (9): 5688–5694. doi:10.4049/jimmunol.166.9.5688. ISSN 0022-1767. PMID 11313410.

[43] Hoebe K, Janssen EM, Kim SO, Alexopoulou L, Flavell RA, Han J, Beutler B (2003-12). "Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways". Nature Immunology. 4 (12): 1223–1229. doi:10.1038/ni1010. ISSN 1529-2916. {{cite journal}}: Check date values in: |date= (help)

[44] Shen H, Tesar BM, Walker WE, Goldstein DR (2008-08-01). "Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation". Journal of Immunology (Baltimore, Md.: 1950). 181 (3): 1849–1858. doi:10.4049/jimmunol.181.3.1849. ISSN 1550-6606. PMC 2507878. PMID 18641322.

[45] Trombetta ES, Ebersold M, Garrett W, Pypaert M, Mellman I (2003-02-28). "Activation of Lysosomal Function During Dendritic Cell Maturation". Science. 299 (5611): 1400–1403. doi:10.1126/science.1080106. ISSN 0036-8075.

[46] Turley SJ, Inaba K, Garrett WS, Ebersold M, Unternaehrer J, Steinman RM, Mellman I (2000-04-21). "Transport of Peptide-MHC Class II Complexes in Developing Dendritic Cells". Science. 288 (5465): 522–527. doi:10.1126/science.288.5465.522. ISSN 0036-8075.

[47] Nair-Gupta P, Baccarini A, Tung N, Seyffer F, Florey O, Huang Y, Banerjee M, Overholtzer M, Roche PA, Tampé R, Brown BD, Amsen D, Whiteheart SW, Blander JM (2014-07). "TLR Signals Induce Phagosomal MHC-I Delivery from the Endosomal Recycling Compartment to Allow Cross-Presentation". Cell. 158 (3): 506–521. doi:10.1016/j.cell.2014.04.054. ISSN 0092-8674. PMC 4212008. PMID 25083866. {{cite journal}}: Check date values in: |date= (help); no-break space character in |first11= at position 6 (help); no-break space character in |first13= at position 7 (help); no-break space character in |first14= at position 3 (help); no-break space character in |first9= at position 5 (help)CS1 maint: PMC format (link)

[48] Paavonen J, Jenkins D, Bosch FX, Naud P, Salmerón J, Wheeler CM, Chow SN, Apter DL, Kitchener HC, Castellsague X, de Carvalho NS, Skinner SR, Harper DM, Hedrick JA, Jaisamrarn U (2007-06-30). "Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial". Lancet (London, England). 369 (9580): 2161–2170. doi:10.1016/S0140-6736(07)60946-5. ISSN 1474-547X. PMID 17602732.

[49] Kundi M (2007-04). "New hepatitis B vaccine formulated with an improved adjuvant system". Expert Review of Vaccines. 6 (2): 133–140. doi:10.1586/14760584.6.2.133. ISSN 1744-8395. PMID 17408363. {{cite journal}}: Check date values in: |date= (help)

[50] Garçon N, Di Pasquale A (2017-01-02). "From discovery to licensure, the Adjuvant System story". Human Vaccines & Immunotherapeutics. 13 (1): 19–33. doi:10.1080/21645515.2016.1225635. ISSN 2164-5515. PMC 5287309. PMID 27636098.{{cite journal}}: CS1 maint: PMC format (link)

[51] Beutler B, Rehli M (2002). "Evolution of the TIR, Tolls and TLRS: Functional Inferences from Computational Biology". Toll-Like Receptor Family Members and Their Ligands. Current Topics in Microbiology and Immunology. Vol. 270. pp. 1–21. doi:10.1007/978-3-642-59430-4_1. ISBN 978-3-642-63975-3. PMID 12467241.

[52] Smirnova I, Poltorak A, Chan EK, McBride C, Beutler B (2000). "Phylogenetic variation and polymorphism at the toll-like receptor 4 locus (TLR4)". Genome Biology. 1 (1): RESEARCH002. doi:10.1186/gb-2000-1-1-research002. PMC 31919. PMID 11104518.

[53] Quach H, Wilson D, Laval G, Patin E, Manry J, Guibert J, et al. (December 2013). "Different selective pressures shape the evolution of Toll-like receptors in human and African great ape populations". Human Molecular Genetics. 22 (23): 4829–4840. doi:10.1093/hmg/ddt335. PMC 3820138. PMID 23851028.

[Barreiro_2009-54] Barreiro LB, Ben-Ali M, Quach H, Laval G, Patin E, Pickrell JK, et al. (July 2009). "Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense". PLOS Genetics. 5 (7): e1000562. doi:10.1371/journal.pgen.1000562. PMC 2702086. PMID 19609346.

[55] Plantinga TS, Ioana M, Alonso S, Izagirre N, Hervella M, Joosten LA, et al. (2012). "The evolutionary history of TLR4 polymorphisms in Europe". Journal of Innate Immunity. 4 (2): 168–175. doi:10.1159/000329492. PMC 6741577. PMID 21968286.

[56] Noreen M, Shah MA, Mall SM, Choudhary S, Hussain T, Ahmed I, Jalil SF, Raza MI (2012-03). "TLR4 polymorphisms and disease susceptibility". Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.] 61 (3): 177–188. doi:10.1007/s00011-011-0427-1. ISSN 1420-908X. PMID 22277994. {{cite journal}}: Check date values in: |date= (help)

[57] Long H, O'Connor BP, Zemans RL, Zhou X, Yang IV, Schwartz DA (2014-04-02). "The Toll-Like Receptor 4 Polymorphism Asp299Gly but Not Thr399Ile Influences TLR4 Signaling and Function". PLOS ONE. 9 (4): e93550. doi:10.1371/journal.pone.0093550. ISSN 1932-6203. PMC 3973565. PMID 24695807.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[58] journals.aai.org https://journals.aai.org/jimmunol/article/188/9/4506/39640. Retrieved 2024-02-20. {{cite web}}: Missing or empty |title= (help)

[59] Ohto U, Yamakawa N, Akashi-Takamura S, Miyake K, Shimizu T (2012-11-23). "Structural Analyses of Human Toll-like Receptor 4 Polymorphisms D299G and T399I". The Journal of Biological Chemistry. 287 (48): 40611–40617. doi:10.1074/jbc.M112.404608. ISSN 0021-9258. PMC 3504774. PMID 23055527.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[60] Akira S, Takeda K (2004-07). "Toll-like receptor signalling". Nature Reviews. Immunology. 4 (7): 499–511. doi:10.1038/nri1391. ISSN 1474-1733. PMID 15229469. {{cite journal}}: Check date values in: |date= (help)

[61] Molteni M, Gemma S, Rossetti C (2016). "The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation". Mediators of Inflammation. 2016. doi:10.1155/2016/6978936. PMID 27293318.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[pmid33057840-62] Ciesielska A, Matyjek M, Kwiatkowska K (February 2021). "TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling". Cellular and Molecular Life Sciences. 78 (4): 1233–1261. doi:10.1007/s00018-020-03656-y. PMC 7904555. PMID 33057840.

[63] Netea MG, Wijmenga C, O'Neill LA (2012-05-18). "Genetic variation in Toll-like receptors and disease susceptibility". Nature Immunology. 13 (6): 535–542. doi:10.1038/ni.2284. ISSN 1529-2916. PMID 22610250.

[64] Chettab K, Fitzsimmons C, Novikov A, Denis M, Phelip C, Mathé D, Choffour PA, Beaumel S, Fourmaux E, Norca P, Kryza D, Evesque A, Jordheim LP, Perrial E, Matera EL (2023). "A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models". Frontiers in Immunology. 14: 1066402. doi:10.3389/fimmu.2023.1066402. ISSN 1664-3224. PMID 37223101.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[65] Richert I, Berchard P, Abbes L, Novikov A, Chettab K, Vandermoeten A, Dumontet C, Karanian M, Kerzerho J, Caroff M, Blay JY, Dutour A (2023-09-19). "A TLR4 Agonist Induces Osteosarcoma Regression by Inducing an Antitumor Immune Response and Reprogramming M2 Macrophages to M1 Macrophages". Cancers. 15 (18): 4635. doi:10.3390/cancers15184635. ISSN 2072-6694. PMID 37760603.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[66] Maruyama K, Selmani Z, Ishii H, Yamaguchi K (2011-03). "Innate immunity and cancer therapy". International Immunopharmacology. 11 (3): 350–357. doi:10.1016/j.intimp.2010.09.012. ISSN 1878-1705. PMID 20955832. {{cite journal}}: Check date values in: |date= (help)

[67] Starnes CO (1992-05-07). "Coley's toxins in perspective". Nature. 357 (6373): 11–12. doi:10.1038/357011a0. ISSN 0028-0836. PMID 1574121.

[68] Tsuji S, Matsumoto M, Takeuchi O, Akira S, Azuma I, Hayashi A, Toyoshima K, Seya T (2000-12). Kaufmann SH (ed.). "Maturation of Human Dendritic Cells by Cell Wall Skeleton of Mycobacterium bovis Bacillus Calmette-Guérin: Involvement of Toll-Like Receptors". Infection and Immunity. 68 (12): 6883–6890. doi:10.1128/IAI.68.12.6883-6890.2000. ISSN 0019-9567. PMC 97794. PMID 11083809. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)

[69] Ryoma Y, Moriya Y, Okamoto M, Kanaya I, Saito M, Sato M (2004-09-01). "Biological Effect of OK-432 (Picibanil) and Possible Application to Dendritic Cell Therapy". Anticancer Research. 24 (5C): 3295–3302. ISSN 0250-7005. PMID 15515424.

[70] academic.oup.com https://academic.oup.com/jnci/article/95/4/316/2520610. Retrieved 2024-02-20. {{cite web}}: Missing or empty |title= (help)

[71] academic.oup.com https://academic.oup.com/jnci/article-abstract/4/5/461/905560. Retrieved 2024-02-20. {{cite web}}: Missing or empty |title= (help)

[72] Berendt MJ, North RJ, Kirstein DP (1978-12-01). "The immunological basis of endotoxin-induced tumor regression. Requirement for a pre-existing state of concomitant anti-tumor immunity". The Journal of Experimental Medicine. 148 (6): 1560–1569. doi:10.1084/jem.148.6.1560. ISSN 0022-1007. PMC 2185097. PMID 309922.

[73] Engelhardt R, Mackensen A, Galanos C (1991-05-15). "Phase I trial of intravenously administered endotoxin (Salmonella abortus equi) in cancer patients". Cancer Research. 51 (10): 2524–2530. ISSN 0008-5472. PMID 2021932.

[74] "Melacine - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2024-02-20.

[75] Bhatia S, Miller NJ, Lu H, Longino NV, Ibrani D, Shinohara MM, Byrd DR, Parvathaneni U, Kulikauskas R, Ter Meulen J, Hsu FJ, Koelle DM, Nghiem P (2019-02-15). "Intratumoral G100, a TLR4 Agonist, Induces Antitumor Immune Responses and Tumor Regression in Patients with Merkel Cell Carcinoma". Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 25 (4): 1185–1195. doi:10.1158/1078-0432.CCR-18-0469. ISSN 1557-3265. PMC 6368904. PMID 30093453.

[76] Halwani AS, Panizo C, Isufi I, Herrera AF, Okada CY, Cull EH, Kis B, Chaves JM, Bartlett NL, Ai W, de la Cruz-Merino L, Bryan LJ, Houot R, Linton K, Briones J (2022-04). "Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma". Leukemia & Lymphoma. 63 (4): 821–833. doi:10.1080/10428194.2021.2010057. ISSN 1029-2403. PMID 34865586. {{cite journal}}: Check date values in: |date= (help)

[77] Flowers C, Panizo C, Isufi I, Herrera AF, Okada C, Cull EH, Kis B, Chaves JM, Bartlett NL, Ai W, de la Cruz-Merino L, Bryan LJ, Houot R, Linton K, Briones J (2017-12-08). "Intratumoral G100 Induces Systemic Immunity and Abscopal Tumor Regression in Patients with Follicular Lymphoma: Results of a Phase 1/ 2 Study Examining G100 Alone and in Combination with Pembrolizumab". Blood. 130: 2771. doi:10.1182/blood.V130.Suppl_1.2771.2771. ISSN 0006-4971.

[78] Rajput S, Volk-Draper LD, Ran S (2013-08). "TLR4 is a novel determinant of the response to paclitaxel in breast cancer". Molecular Cancer Therapeutics. 12 (8): 1676–1687. doi:10.1158/1535-7163.MCT-12-1019. ISSN 1538-8514. PMC 3742631. PMID 23720768. {{cite journal}}: Check date values in: |date= (help)

[79] Flowers C, Panizo C, Isufi I, Herrera AF, Okada C, Cull EH, Kis B, Chaves JM, Bartlett NL, Ai W, de la Cruz-Merino L, Bryan LJ, Houot R, Linton K, Briones J (2017-12-08). "Intratumoral G100 Induces Systemic Immunity and Abscopal Tumor Regression in Patients with Follicular Lymphoma: Results of a Phase 1/ 2 Study Examining G100 Alone and in Combination with Pembrolizumab". Blood. 130: 2771. doi:10.1182/blood.V130.Suppl_1.2771.2771. ISSN 0006-4971.

[80] Zhang R, Zhao J, Xu J, Jiao DX, Wang J, Gong ZQ, Jia JH (2017-10). "Andrographolide suppresses proliferation of human colon cancer SW620 cells through the TLR4/NF-κB/MMP-9 signaling pathway". Oncology Letters. 14 (4): 4305–4310. doi:10.3892/ol.2017.6669. ISSN 1792-1074. PMC 5604146. PMID 28943944. {{cite journal}}: Check date values in: |date= (help)

[81] Wang CH, Wang PJ, Hsieh YC, Lo S, Lee YC, Chen YC, Tsai CH, Chiu WC, Chu-Sung Hu S, Lu CW, Yang YF, Chiu CC, Ou-Yang F, Wang YM, Hou MF (2018-02-01). "Resistin facilitates breast cancer progression via TLR4-mediated induction of mesenchymal phenotypes and stemness properties". Oncogene. 37 (5): 589–600. doi:10.1038/onc.2017.357. ISSN 1476-5594. PMID 28991224.

[82] Kelly MG, Alvero AB, Chen R, Silasi DA, Abrahams VM, Chan S, Visintin I, Rutherford T, Mor G (2006-04-01). "TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer". Cancer Research. 66 (7): 3859–3868. doi:10.1158/0008-5472.CAN-05-3948. ISSN 0008-5472. PMID 16585214.

[83] Jang GY, Lee JW, Kim YS, Lee SE, Han HD, Hong KJ, Kang TH, Park YM (2020-12). "Interactions between tumor-derived proteins and Toll-like receptors". Experimental & Molecular Medicine. 52 (12): 1926–1935. doi:10.1038/s12276-020-00540-4. ISSN 2092-6413. PMC 8080774. PMID 33299138. {{cite journal}}: Check date values in: |date= (help)

[84] Khademalhosseini M, Arababadi MK (2019-05-01). "Toll-like receptor 4 and breast cancer: an updated systematic review". Breast Cancer. 26 (3): 265–271. doi:10.1007/s12282-018-00935-2. ISSN 1880-4233.

[85] Roh JS, Sohn DH (2018-08). "Damage-Associated Molecular Patterns in Inflammatory Diseases". Immune Network. 18 (4): e27. doi:10.4110/in.2018.18.e27. ISSN 1598-2629. PMC 6117512. PMID 30181915. {{cite journal}}: Check date values in: |date= (help)

[86] Jang GY, Lee JW, Kim YS, Lee SE, Han HD, Hong KJ, Kang TH, Park YM (2020-12). "Interactions between tumor-derived proteins and Toll-like receptors". Experimental & Molecular Medicine. 52 (12): 1926–1935. doi:10.1038/s12276-020-00540-4. ISSN 2092-6413. PMC 8080774. PMID 33299138. {{cite journal}}: Check date values in: |date= (help)

[87] Hernandez C, Huebener P, Schwabe RF (2016-11-17). "Damage-associated molecular patterns in cancer: a double-edged sword". Oncogene. 35 (46): 5931–5941. doi:10.1038/onc.2016.104. ISSN 1476-5594. PMC 5119456. PMID 27086930.

[88] Zhu L, Yuan H, Jiang T, Wang R, Ma H, Zhang S (2013-12-20). "Association of TLR2 and TLR4 Polymorphisms with Risk of Cancer: A Meta-Analysis". PLoS ONE. 8 (12): e82858. doi:10.1371/journal.pone.0082858. ISSN 1932-6203. PMC 3869723. PMID 24376595.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[89] Vaure C, Liu Y (2014). "A Comparative Review of Toll-Like Receptor 4 Expression and Functionality in Different Animal Species". Frontiers in Immunology. 5. doi:10.3389/fimmu.2014.00316/full. ISSN 1664-3224.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[90] Wardill HR, Van Sebille YZ, Mander KA, Gibson RJ, Logan RM, Bowen JM, Sonis ST (2015-02). "Toll-like receptor 4 signaling: a common biological mechanism of regimen-related toxicities: an emerging hypothesis for neuropathy and gastrointestinal toxicity". Cancer Treatment Reviews. 41 (2): 122–128. doi:10.1016/j.ctrv.2014.11.005. ISSN 1532-1967. PMID 25512119. {{cite journal}}: Check date values in: |date= (help)

[91] Molteni M, Gemma S, Rossetti C (2016). "The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation". Mediators of Inflammation. 2016: 6978936. doi:10.1155/2016/6978936. ISSN 1466-1861. PMC 4887650. PMID 27293318.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[92] Tahara K, Kim HD, Jin JJ, Maxwell JA, Li L, Fukuchi Ki (2006-11). "Role of toll-like receptor signalling in Abeta uptake and clearance". Brain: A Journal of Neurology. 129 (Pt 11): 3006–3019. doi:10.1093/brain/awl249. ISSN 1460-2156. PMC 2445613. PMID 16984903. {{cite journal}}: Check date values in: |date= (help)

[93] Buchanan MM, Hutchinson M, Watkins LR, Yin H (2010-7). "Toll-like Receptor 4 in CNS Pathologies". Journal of neurochemistry. 114 (1): 13–27. doi:10.1111/j.1471-4159.2010.06736.x. ISSN 0022-3042. PMC 2909662. PMID 20402965. {{cite journal}}: Check date values in: |date= (help)

[94] Qin Y, Liu Y, Hao W, Decker Y, Tomic I, Menger MD, Liu C, Fassbender K (2016-10-15). "Stimulation of TLR4 Attenuates Alzheimer's Disease-Related Symptoms and Pathology in Tau-Transgenic Mice". Journal of Immunology (Baltimore, Md.: 1950). 197 (8): 3281–3292. doi:10.4049/jimmunol.1600873. ISSN 1550-6606. PMID 27605009.

[95] Gambuzza M, Licata N, Palella E, Celi D, Foti Cuzzola V, Italiano D, Marino S, Bramanti P (2011-10-28). "Targeting Toll-like receptors: emerging therapeutics for multiple sclerosis management". Journal of Neuroimmunology. 239 (1–2): 1–12. doi:10.1016/j.jneuroim.2011.08.010. ISSN 1872-8421. PMID 21889214.

[96] Buchanan MM, Hutchinson M, Watkins LR, Yin H (2010-7). "Toll-like Receptor 4 in CNS Pathologies". Journal of neurochemistry. 114 (1): 13–27. doi:10.1111/j.1471-4159.2010.06736.x. ISSN 0022-3042. PMC 2909662. PMID 20402965. {{cite journal}}: Check date values in: |date= (help)

[97] Rannikko EH, Weber SS, Kahle PJ (2015-09-07). "Exogenous α-synuclein induces toll-like receptor 4 dependent inflammatory responses in astrocytes". BMC neuroscience. 16: 57. doi:10.1186/s12868-015-0192-0. ISSN 1471-2202. PMC 4562100. PMID 26346361.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[98] Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, Bode B, Manietta N, Walter J, Schulz-Schuffer W, Fassbender K (2007). "Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease". Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology. 20 (6): 947–956. doi:10.1159/000110455. ISSN 1015-8987. PMID 17982277.

[99] Land WG (2015-02). "The Role of Damage-Associated Molecular Patterns in Human Diseases: Part I - Promoting inflammation and immunity". Sultan Qaboos University Medical Journal. 15 (1): e9–e21. ISSN 2075-051X. PMC 4318613. PMID 25685392. {{cite journal}}: Check date values in: |date= (help)

[100] Festoff BW, Sajja RK, van Dreden P, Cucullo L (2016-08-24). "HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer's disease". Journal of Neuroinflammation. 13 (1): 194. doi:10.1186/s12974-016-0670-z. ISSN 1742-2094. PMC 4995775. PMID 27553758.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[101] Chaves ML, Camozzato AL, Ferreira ED, Piazenski I, Kochhann R, Dall'Igna O, Mazzini GS, Souza DO, Portela LV (2010-01-27). "Serum levels of S100B and NSE proteins in Alzheimer's disease patients". Journal of Neuroinflammation. 7: 6. doi:10.1186/1742-2094-7-6. ISSN 1742-2094. PMC 2832635. PMID 20105309.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[102] Yang Y, Han C, Guo L, Guan Q (2018-04). "High expression of the HMGB1-TLR4 axis and its downstream signaling factors in patients with Parkinson's disease and the relationship of pathological staging". Brain and Behavior. 8 (4): e00948. doi:10.1002/brb3.948. ISSN 2162-3279. PMC 5893335. PMID 29670828. {{cite journal}}: Check date values in: |date= (help)

[103] Wu L, Xian X, Xu G, Tan Z, Dong F, Zhang M, Zhang F (2022-08-21). "Toll-Like Receptor 4: A Promising Therapeutic Target for Alzheimer's Disease". Mediators of Inflammation. 2022: 1–20. doi:10.1155/2022/7924199. ISSN 1466-1861.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[104] Leitner GR, Wenzel TJ, Marshall N, Gates EJ, Klegeris A (2019-10). "Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders". Expert Opinion on Therapeutic Targets. 23 (10): 865–882. doi:10.1080/14728222.2019.1676416. ISSN 1744-7631. PMID 31580163. {{cite journal}}: Check date values in: |date= (help)

[105] Michaud JP, Hallé M, Lampron A, Thériault P, Préfontaine P, Filali M, Tribout-Jover P, Lanteigne AM, Jodoin R, Cluff C, Brichard V, Palmantier R, Pilorget A, Larocque D, Rivest S (2013-01-29). "Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer's disease-related pathology". Proceedings of the National Academy of Sciences of the United States of America. 110 (5): 1941–1946. doi:10.1073/pnas.1215165110. ISSN 1091-6490. PMC 3562771. PMID 23322736.

[106] Leitner GR, Wenzel TJ, Marshall N, Gates EJ, Klegeris A (2019-10). "Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders". Expert Opinion on Therapeutic Targets. 23 (10): 865–882. doi:10.1080/14728222.2019.1676416. ISSN 1744-7631. PMID 31580163. {{cite journal}}: Check date values in: |date= (help)

[pmid15836969-107] Shavit Y, Wolf G, Goshen I, Livshits D, Yirmiya R (May 2005). "Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance". Pain. 115 (1–2): 50–59. doi:10.1016/j.pain.2005.02.003. PMID 15836969. S2CID 7286123.

[pmid20615556-108] Mohan S, Davis RL, DeSilva U, Stevens CW (October 2010). "Dual regulation of mu opioid receptors in SK-N-SH neuroblastoma cells by morphine and interleukin-1β: evidence for opioid-immune crosstalk". Journal of Neuroimmunology. 227 (1–2): 26–34. doi:10.1016/j.jneuroim.2010.06.007. PMC 2942958. PMID 20615556.

[pmid19607972-109] Komatsu T, Sakurada S, Katsuyama S, Sanai K, Sakurada T (2009). Mechanism of allodynia evoked by intrathecal morphine-3-glucuronide in mice. International Review of Neurobiology. Vol. 85. pp. 207–19. doi:10.1016/S0074-7742(09)85016-2. ISBN 978-0-12-374893-5. PMID 19607972.

[pmid19833175-110] Lewis SS, Hutchinson MR, Rezvani N, Loram LC, Zhang Y, Maier SF, et al. (January 2010). "Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta". Neuroscience. 165 (2): 569–583. doi:10.1016/j.neuroscience.2009.10.011. PMC 2795035. PMID 19833175.

[pmid21081778-111] Shen CH, Tsai RY, Shih MS, Lin SL, Tai YH, Chien CC, Wong CS (February 2011). "Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats". Anesthesia and Analgesia. 112 (2): 454–459. doi:10.1213/ANE.0b013e3182025b15. PMID 21081778. S2CID 12295407.

[pmid20974246-112] Hook MA, Washburn SN, Moreno G, Woller SA, Puga D, Lee KH, Grau JW (February 2011). "An IL-1 receptor antagonist blocks a morphine-induced attenuation of locomotor recovery after spinal cord injury". Brain, Behavior, and Immunity. 25 (2): 349–359. doi:10.1016/j.bbi.2010.10.018. PMC 3025088. PMID 20974246.

[pmid19762094-113] Watkins LR, Hutchinson MR, Rice KC, Maier SF (November 2009). "The "toll" of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia". Trends in Pharmacological Sciences. 30 (11): 581–591. doi:10.1016/j.tips.2009.08.002. PMC 2783351. PMID 19762094.

[pmid18662331-114] Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, et al. (July 2008). "Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4)". The European Journal of Neuroscience. 28 (1): 20–29. doi:10.1111/j.1460-9568.2008.06321.x. PMC 2588470. PMID 18662331.

[pmid18599265-115] Hutchinson MR, Coats BD, Lewis SS, Zhang Y, Sprunger DB, Rezvani N, et al. (November 2008). "Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia". Brain, Behavior, and Immunity. 22 (8): 1178–1189. doi:10.1016/j.bbi.2008.05.004. PMC 2783238. PMID 18599265.

[pmid20178837-116] Hutchinson MR, Lewis SS, Coats BD, Rezvani N, Zhang Y, Wieseler JL, et al. (May 2010). "Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences". Neuroscience. 167 (3): 880–893. doi:10.1016/j.neuroscience.2010.02.011. PMC 2854318. PMID 20178837.

[pmid19799935-117] Lin SL, Tsai RY, Tai YH, Cherng CH, Wu CT, Yeh CC, Wong CS (February 2010). "Ultra-low dose naloxone upregulates interleukin-10 expression and suppresses neuroinflammation in morphine-tolerant rat spinal cords". Behavioural Brain Research. 207 (1): 30–36. doi:10.1016/j.bbr.2009.09.034. PMID 19799935. S2CID 5128970.

[118] "Neuroscience: Making morphine work better". Nature. 484 (7395): 419. 26 April 2012. Bibcode:2012Natur.484Q.419.. doi:10.1038/484419a. S2CID 52805136.

[urlcen.acs.org-119] Drahl C (22 August 2012). "Small Molecules Target Toll-Like Receptors". Chemical & Engineering News.

[120] Yang H, Wang H, Ju Z, Ragab AA, Lundbäck P, Long W, Valdes-Ferrer SI, He M, Pribis JP, Li J, Lu B, Gero D, Szabo C, Antoine DJ, Harris HE (2015-01-05). "MD-2 is required for disulfide HMGB1–dependent TLR4 signaling". Journal of Experimental Medicine. 212 (1): 5–14. doi:10.1084/jem.20141318. ISSN 1540-9538. PMC 4291531. PMID 25559892.{{cite journal}}: CS1 maint: PMC format (link)

[121] Manček‐Keber Mateja, Jerala R (2015-02). "Postulates for validating TLR4 agonists". European Journal of Immunology. 45 (2): 356–370. doi:10.1002/eji.201444462. ISSN 0014-2980. {{cite journal}}: Check date values in: |date= (help); Vancouver style error: non-Latin character in name 1 (help)

[122] Kim HM, Kim YM (2018-10). "HMGB1: LPS Delivery Vehicle for Caspase-11-Mediated Pyroptosis". Immunity. 49 (4): 582–584. doi:10.1016/j.immuni.2018.09.021. {{cite journal}}: Check date values in: |date= (help)

[123] Romerio A, Peri F (2020). "Increasing the Chemical Variety of Small-Molecule-Based TLR4 Modulators: An Overview". Frontiers in Immunology. 11: 1210. doi:10.3389/fimmu.2020.01210. PMC 7381287. PMID 32765484.

[pmid20381591-124] Hutchinson MR, Loram LC, Zhang Y, Shridhar M, Rezvani N, Berkelhammer D, et al. (June 2010). "Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity". Neuroscience. 168 (2): 551–563. doi:10.1016/j.neuroscience.2010.03.067. PMC 2872682. PMID 20381591.

[125] Chen F, Zou L, Williams B, Chao W (November 2021). "Targeting Toll-Like Receptors in Sepsis: From Bench to Clinical Trials". Antioxidants & Redox Signaling. 35 (15): 1324–1339. doi:10.1089/ars.2021.0005. PMC 8817700. PMID 33588628.

[pmid22776604-126] Jia ZJ, Wu FX, Huang QH, Liu JM (April 2012). "[Toll-like receptor 4: the potential therapeutic target for neuropathic pain]". Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae. 34 (2): 168–173. doi:10.3881/j.issn.1000-503X.2012.02.013. PMID 22776604.

[pmid28007523-127] Lan X, Han X, Li Q, Li Q, Gao Y, Cheng T, et al. (March 2017). "Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia". Brain, Behavior, and Immunity. 61: 326–339. doi:10.1016/j.bbi.2016.12.012. PMC 5453178. PMID 28007523.

[pmid31697454-128] Kaieda A, Takahashi M, Fukuda H, Okamoto R, Morimoto S, Gotoh M, et al. (December 2019). "Structure-Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]Pyridin-2-one-Based p38 MAP Kinase Inhibitors: Part 2". ChemMedChem. 14 (24): 2093–2101. doi:10.1002/cmdc.201900373. PMID 31697454. S2CID 207951964.

[pmid19679181-129] Hutchinson MR, Zhang Y, Shridhar M, Evans JH, Buchanan MM, Zhao TX, et al. (January 2010). "Evidence that opioids may have toll-like receptor 4 and MD-2 effects". Brain, Behavior, and Immunity. 24 (1): 83–95. doi:10.1016/j.bbi.2009.08.004. PMC 2788078. PMID 19679181.

[130] Speer EM, Dowling DJ, Ozog LS, Xu J, Yang J, Kennady G, Levy O (May 2017). "Pentoxifylline inhibits TLR- and inflammasome-mediated in vitro inflammatory cytokine production in human blood with greater efficacy and potency in newborns". Pediatric Research. 81 (5): 806–816. doi:10.1038/pr.2017.6. PMID 28072760. S2CID 47210724.

[131] Schüller SS, Wisgrill L, Herndl E, Spittler A, Förster-Waldl E, Sadeghi K, et al. (August 2017). "Pentoxifylline modulates LPS-induced hyperinflammation in monocytes of preterm infants in vitro". Pediatric Research. 82 (2): 215–225. doi:10.1038/pr.2017.41. PMID 28288151. S2CID 24897100.

[pmid23776545-132] Neal MD, Jia H, Eyer B, Good M, Guerriero CJ, Sodhi CP, et al. (2013). "Discovery and validation of a new class of small molecule Toll-like receptor 4 (TLR4) inhibitors". PLOS ONE. 8 (6): e65779. Bibcode:2013PLoSO...865779N. doi:10.1371/journal.pone.0065779. PMC 3680486. PMID 23776545.

[133] Impellizzeri D, Campolo M, Di Paola R, Bruschetta G, de Stefano D, Esposito E, Cuzzocrea S (2015). "Ultramicronized palmitoylethanolamide reduces inflammation an a Th1-mediated model of colitis". European Journal of Inflammation. 13: 14–31. doi:10.1177/1721727X15575869. S2CID 79398556.

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 {{Short description|Protein-coding gene in the species Homo sapiens}}
 {{Infobox_gene}}
-'''Toll-like receptor 4''' (TLR4) is a transmembrane [[protein]] of approximately 95 kDa that is encoded by the ''TLR4'' [[gene]]. TLR4 is also designated as '''CD284''' ([[cluster of differentiation]] 284).
+'''Toll-like receptor 4''' (TLR4), also designated as '''CD284''' ([[cluster of differentiation]] 284), is a transmembrane [[protein]] of approximately 95 kDa that is encoded by the ''TLR4'' [[gene]].
 '''TLR4''' belongs to the [[toll-like receptor]] family which is representative of the [[pattern recognition receptor]]<nowiki/>s (PRR), so named for their ability to recognize evolutionarily conserved components of microorganisms (bacteria, viruses, fungi and parasites) called [[Pathogen-associated molecular pattern|pathogen-associated molecular patterns]] (PAMPs). The recognition of a PAMP by a PRR triggers rapid activation of the innate immunity essential to fight infectious diseases.<ref name="pmid25071777">{{cite journal | vauthors = Vaure C, Liu Y | title = A comparative review of toll-like receptor 4 expression and functionality in different animal species | journal = Frontiers in Immunology | volume = 5 | page = 316 | date = 2014 | pmid = 25071777 | pmc = 4090903 | doi = 10.3389/fimmu.2014.00316 | doi-access = free }}</ref>
-TLR4 is expressed in immune cells mainly of myeloid origin, including monocytes, macrophages and dendritic cells (DC).<ref>{{cite journal | vauthors = Vaure C, Liu Y | title = A comparative review of toll-like receptor 4 expression and functionality in different animal species | journal = Frontiers in Immunology | volume = 5 | pages = 316 | date = 2014 | pmid = 25071777 | pmc = 4090903 | doi = 10.3389/fimmu.2014.00316 | doi-access = free }}</ref> It is also expressed at a lower level on some non-immune cells, including epithelium, endothelium, placental cells and beta cells in Langerhans islets. Most myeloid cells express also high amounts of plasma membrane-anchored CD14, which facilitates the activation of TLR4 by LPS and controls the subsequent internalization of the LPS-activated TLR4 important for receptor signaling and degradation.<ref>{{cite book | vauthors = Mahnke K, Becher E, Ricciardi-Castagnoli P, Luger TA, Schwarz T, Grabbe S | chapter = CD14 is Expressed by Subsets of Murine Dendritic Cells and Upregulated by Lipopolysaccharide |date=1997 | title =Dendritic Cells in Fundamental and Clinical Immunology |volume=417 |pages=145–159 | veditors = Ricciardi-Castagnoli P |place=Boston, MA |publisher=Springer US |doi=10.1007/978-1-4757-9966-8_25 |isbn=978-1-4757-9968-2 }}</ref><ref>{{cite journal | vauthors = Sabroe I, Jones EC, Usher LR, Whyte MK, Dower SK | title = Toll-like receptor (TLR)2 and TLR4 in human peripheral blood granulocytes: a critical role for monocytes in leukocyte lipopolysaccharide responses | journal = Journal of Immunology | volume = 168 | issue = 9 | pages = 4701–4710 | date = May 2002 | pmid = 11971020 | doi = 10.4049/jimmunol.168.9.4701 }}</ref>
+TLR4 is expressed in immune cells mainly of myeloid origin, including monocytes, macrophages and dendritic cells (DC).<ref>{{cite journal | vauthors = Vaure C, Liu Y | title = A comparative review of toll-like receptor 4 expression and functionality in different animal species | journal = Frontiers in Immunology | volume = 5 | pages = 316 | date = 2014 | pmid = 25071777 | pmc = 4090903 | doi = 10.3389/fimmu.2014.00316 | doi-access = free }}</ref> It is also expressed at a lower level on some non-immune cells, including epithelium, endothelium, placental cells and beta cells in Langerhans islets. Most myeloid cells express also high amounts of plasma membrane-anchored [[CD14]], which facilitates the activation of TLR4 by LPS and controls the subsequent internalization of the LPS-activated TLR4 important for receptor signaling and degradation.<ref>{{cite book | vauthors = Mahnke K, Becher E, Ricciardi-Castagnoli P, Luger TA, Schwarz T, Grabbe S | chapter = CD14 is Expressed by Subsets of Murine Dendritic Cells and Upregulated by Lipopolysaccharide |date=1997 | title =Dendritic Cells in Fundamental and Clinical Immunology |volume=417 |pages=145–159 | veditors = Ricciardi-Castagnoli P |place=Boston, MA |publisher=Springer US |doi=10.1007/978-1-4757-9966-8_25 |isbn=978-1-4757-9968-2 }}</ref><ref>{{cite journal | vauthors = Sabroe I, Jones EC, Usher LR, Whyte MK, Dower SK | title = Toll-like receptor (TLR)2 and TLR4 in human peripheral blood granulocytes: a critical role for monocytes in leukocyte lipopolysaccharide responses | journal = Journal of Immunology | volume = 168 | issue = 9 | pages = 4701–4710 | date = May 2002 | pmid = 11971020 | doi = 10.4049/jimmunol.168.9.4701 }}</ref>
-TLR4 is activated by lipopolysaccharide (LPS), a major component of the outer membrane of [[Gram-negative bacteria]] and some [[Gram-positive bacteria]]. TLR4 can also be activated by endogenous compounds called damage-associated molecular patterns (DAMPs), including high mobility group box protein 1 (HMGB1) and hyaluronic acid. These compounds are released during tissue injury and can activate TLR4 in non-infectious conditions to induce tissue repair.<ref name="pmid25559892">{{cite journal | vauthors = Yang H, Wang H, Ju Z, Ragab AA, Lundbäck P, Long W, Valdes-Ferrer SI, He M, Pribis JP, Li J, Lu B, Gero D, Szabo C, Antoine DJ, Harris HE, Golenbock DT, Meng J, Roth J, Chavan SS, Andersson U, Billiar TR, Tracey KJ, Al-Abed Y | display-authors = 6 | title = MD-2 is required for disulfide HMGB1-dependent TLR4 signaling | journal = The Journal of Experimental Medicine | volume = 212 | issue = 1 | pages = 5–14 | date = January 2015 | pmid = 25559892 | pmc = 4291531 | doi = 10.1084/jem.20141318 }}</ref><ref>{{cite journal | vauthors = Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, Prestwich GD, Mascarenhas MM, Garg HG, Quinn DA, Homer RJ, Goldstein DR, Bucala R, Lee PJ, Medzhitov R, Noble PW | display-authors = 6 | title = Regulation of lung injury and repair by Toll-like receptors and hyaluronan | journal = Nature Medicine | volume = 11 | issue = 11 | pages = 1173–1179 | date = November 2005 | pmid = 16244651 | doi = 10.1038/nm1315 }}</ref><ref>{{cite journal | vauthors = Fang H, Ang B, Xu X, Huang X, Wu Y, Sun Y, Wang W, Li N, Cao X, Wan T | display-authors = 6 | title = TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells | journal = Cellular & Molecular Immunology | volume = 11 | issue = 2 | pages = 150–159 | date = March 2014 | pmid = 24362470 | pmc = 4003380 | doi = 10.1038/cmi.2013.59 }}</ref><ref>{{cite journal | vauthors = Hernandez C, Huebener P, Schwabe RF | title = Damage-associated molecular patterns in cancer: a double-edged sword | journal = Oncogene | volume = 35 | issue = 46 | pages = 5931–5941 | date = November 2016 | pmid = 27086930 | pmc = 5119456 | doi = 10.1038/onc.2016.104 }}</ref><ref>{{cite journal | vauthors = Jang GY, Lee JW, Kim YS, Lee SE, Han HD, Hong KJ, Kang TH, Park YM | display-authors = 6 | title = Interactions between tumor-derived proteins and Toll-like receptors | journal = Experimental & Molecular Medicine | volume = 52 | issue = 12 | pages = 1926–1935 | date = December 2020 | pmid = 33299138 | pmc = 8080774 | doi = 10.1038/s12276-020-00540-4 }}</ref> Apart from LPS and its derivatives, up to 30 natural TLR4 agonists with diverse chemical structures have been postulated. However, besides DAMPs, the others have not demonstrated to be direct activators of TLR4 and could therefore act as chaperones for TLR4 or as promoters of LPS internalization.<ref name="pmid25559892" /><ref>{{cite journal | vauthors = Manček-Keber M, Jerala R | title = Postulates for validating TLR4 agonists | journal = European Journal of Immunology | volume = 45 | issue = 2 | pages = 356–370 | date = February 2015 | pmid = 25476977 | doi = 10.1002/eji.201444462 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kim HM, Kim YM | title = HMGB1: LPS Delivery Vehicle for Caspase-11-Mediated Pyroptosis | journal = Immunity | volume = 49 | issue = 4 | pages = 582–584 | date = October 2018 | pmid = 30332623 | doi = 10.1016/j.immuni.2018.09.021 | doi-access = free }}</ref>
+The main ligands for TLR4 are [[Lipopolysaccharide|lipopolysaccharides]] (LPS), the major components of the outer membrane of [[Gram-negative bacteria]] and some [[Gram-positive bacteria]]. TLR4 can also be activated by endogenous compounds called damage-associated molecular patterns ([[DAMPs]]), including high mobility group box protein 1 ([[HMGB1]]), [[S100 protein|S100]] proteins, or [[Histone|histones]]. These compounds are released during tissue injury and by dying or necrotic cells <ref name="pmid25559892">{{cite journal |display-authors=6 |vauthors=Yang H, Wang H, Ju Z, Ragab AA, Lundbäck P, Long W, Valdes-Ferrer SI, He M, Pribis JP, Li J, Lu B, Gero D, Szabo C, Antoine DJ, Harris HE, Golenbock DT, Meng J, Roth J, Chavan SS, Andersson U, Billiar TR, Tracey KJ, Al-Abed Y |date=January 2015 |title=MD-2 is required for disulfide HMGB1-dependent TLR4 signaling |journal=The Journal of Experimental Medicine |volume=212 |issue=1 |pages=5–14 |doi=10.1084/jem.20141318 |pmc=4291531 |pmid=25559892}}</ref><ref name=":0">{{cite journal |display-authors=6 |vauthors=Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, Prestwich GD, Mascarenhas MM, Garg HG, Quinn DA, Homer RJ, Goldstein DR, Bucala R, Lee PJ, Medzhitov R, Noble PW |date=November 2005 |title=Regulation of lung injury and repair by Toll-like receptors and hyaluronan |journal=Nature Medicine |volume=11 |issue=11 |pages=1173–1179 |doi=10.1038/nm1315 |pmid=16244651}}</ref><ref name=":1">{{cite journal |display-authors=6 |vauthors=Fang H, Ang B, Xu X, Huang X, Wu Y, Sun Y, Wang W, Li N, Cao X, Wan T |date=March 2014 |title=TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells |journal=Cellular & Molecular Immunology |volume=11 |issue=2 |pages=150–159 |doi=10.1038/cmi.2013.59 |pmc=4003380 |pmid=24362470}}</ref><ref name=":2">{{cite journal |vauthors=Hernandez C, Huebener P, Schwabe RF |date=November 2016 |title=Damage-associated molecular patterns in cancer: a double-edged sword |journal=Oncogene |volume=35 |issue=46 |pages=5931–5941 |doi=10.1038/onc.2016.104 |pmc=5119456 |pmid=27086930}}</ref><ref name=":3">{{cite journal | vauthors = Jang GY, Lee JW, Kim YS, Lee SE, Han HD, Hong KJ, Kang TH, Park YM | display-authors = 6 | title = Interactions between tumor-derived proteins and Toll-like receptors | journal = Experimental & Molecular Medicine | volume = 52 | issue = 12 | pages = 1926–1935 | date = December 2020 | pmid = 33299138 | pmc = 8080774 | doi = 10.1038/s12276-020-00540-4 }}</ref>.
 == Function ==
+The '''first function''' described for TLR4 was the recognition of exogenous molecules from pathogens (PAMPs), in particular LPS molecules from gram-negative bacteria <ref>{{Cite journal |last=Molteni |first=Monica |last2=Gemma |first2=Sabrina |last3=Rossetti |first3=Carlo |date=2016 |title=The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887650/ |journal=Mediators of Inflammation |volume=2016 |pages=6978936 |doi=10.1155/2016/6978936 |issn=0962-9351 |pmc=4887650 |pmid=27293318}}</ref>. As [[pattern recognition receptor]], TLR4 plays a fundamental role in pathogen recognition and activation of [[innate immunity]] which is the first line of defense against invading micro-organisms. During infection, TLR4 responds to the LPS present in tissues and the bloodstream and triggers pro-inflammatory reactions facilitating eradication of the invading bacteria <ref>{{Cite journal |last=Molteni |first=Monica |last2=Gemma |first2=Sabrina |last3=Rossetti |first3=Carlo |date=2016 |title=The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887650/ |journal=Mediators of Inflammation |volume=2016 |pages=6978936 |doi=10.1155/2016/6978936 |issn=0962-9351 |pmc=4887650 |pmid=27293318}}</ref>.
-TLR4 is a member of the [[toll-like receptor]] (TLR) family, which plays a fundamental role in pathogen recognition and activation of [[innate immunity]]. They recognize pathogen-associated molecular patterns ([[Pathogen-associated molecular pattern|PAMP]]s) that are expressed on infectious agents, and mediate the production of [[cytokine]]s necessary for the development of effective immunity. TLRs are highly conserved from plants to ''[[Drosophila]]'' to humans and share structural and functional similarities.
+TLR4 is also involved in the recognition of '''endogenous DAMP''' molecules leading to different signaling outcomes than PAMPs, both quantitatively and qualitatively <ref>{{Cite journal |last=Roh |first=Jong Seong |last2=Sohn |first2=Dong Hyun |date=2018-08-13 |title=Damage-Associated Molecular Patterns in Inflammatory Diseases |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117512/ |journal=Immune Network |volume=18 |issue=4 |pages=e27 |doi=10.4110/in.2018.18.e27 |issn=1598-2629 |pmc=6117512 |pmid=30181915}}</ref><ref>{{Cite journal |last=Jang |first=Gun-Young |last2=Lee |first2=Ji Won |last3=Kim |first3=Young Seob |last4=Lee |first4=Sung Eun |last5=Han |first5=Hee Dong |last6=Hong |first6=Kee-Jong |last7=Kang |first7=Tae Heung |last8=Park |first8=Yeong-Min |date=2020-12 |title=Interactions between tumor-derived proteins and Toll-like receptors |url=https://pubmed.ncbi.nlm.nih.gov/33299138/ |journal=Experimental & Molecular Medicine |volume=52 |issue=12 |pages=1926–1935 |doi=10.1038/s12276-020-00540-4 |issn=2092-6413 |pmc=8080774 |pmid=33299138}}</ref>. Through TLR4, DAMPs can activate TLR4 in non-infectious conditions to induce tissue repair and the activation of proinflammatory responses <ref name="pmid25559892" /><ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":3" />. Generally, inflammation has a protective role. It is a complex and coordinated process followed by the induction of resolution pathways that restore tissue integrity and function. However, in some cases, an excessive and/or poorly regulated inflammatory response to DAMPs can be detrimental to the organism, accelerating the development or progression of pathologies such as a number of cancers and neurodegenerative diseases (as discussed below).
-The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in [[placenta]], and in [[myelomonocytic]] subpopulation of the [[leukocytes]].
+TLR4 binds LPS with the help of [[Lipopolysaccharide binding protein|LPS-binding protein]] (LBP) and CD14, and an indispensable contribution of the MD-2 protein stably associated with the extracellular fragment of the receptor <ref>{{Cite journal |last=Tsukamoto |first=Hiroki |last2=Takeuchi |first2=Shino |last3=Kubota |first3=Kanae |last4=Kobayashi |first4=Yohei |last5=Kozakai |first5=Sao |last6=Ukai |first6=Ippo |last7=Shichiku |first7=Ayumi |last8=Okubo |first8=Misaki |last9=Numasaki |first9=Muneo |last10=Kanemitsu |first10=Yoshitomi |last11=Matsumoto |first11=Yotaro |last12=Nochi |first12=Tomonori |last13=Watanabe |first13=Kouichi |last14=Aso |first14=Hisashi |last15=Tomioka |first15=Yoshihisa |date=2018-06 |title=Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent Toll-like receptor 4 internalization and LPS-induced TBK1–IKKϵ–IRF3 axis activation |url=https://linkinghub.elsevier.com/retrieve/pii/S0021925820338564 |journal=Journal of Biological Chemistry |language=en |volume=293 |issue=26 |pages=10186–10201 |doi=10.1074/jbc.M117.796631 |pmc=PMC6028956 |pmid=29760187}}</ref>. TLR4 signaling responds to signals by forming a complex using an extracellular [[Leucine-rich repeat|leucine-rich repeat domain]] (LRR) and an intracellular [[Toll-Interleukin receptor|toll/interleukin-1 receptor]] (TIR) domain. LPS stimulation induces a series of interactions with several accessory proteins which form the TLR4 complex on the cell surface. LPS recognition is initiated by an LPS binding to an [[Lipopolysaccharide binding protein|LBP protein]]. This LPS-LBP complex transfers the LPS to [[CD14]] which is a glycosylphosphatidylinositol-anchored membrane protein that binds the LPS-LBP complex and facilitates the transfer of LPS to [[Lymphocyte antigen 96|MD-2 protein]], which is associated with the extracellular domain of TLR4. LPS binding promotes the dimerization of TLR4/MD-2 complex. The conformational changes of the TLR4 induce the recruitment of intracellular adaptor proteins containing the TIR domain which is necessary to activate the downstream signaling pathway.
-It cooperates with [[LY96]] (also referred as MD-2) and [[CD14]] to mediate in [[signal transduction]] events induced by [[lipopolysaccharide]] (LPS)<ref>{{cite web|title=O00206 (TLR4_HUMAN)|url=https://www.uniprot.org/uniprot/O00206|publisher=Uniprot}}</ref>  found in most [[gram-negative bacteria]]. Mutations in this gene have been associated with differences in LPS responsiveness.
+The binding of an LPS molecule to the TLR4/MD-2 complex involves acyl chains and phosphate groups of lipid A, the conserved part of LPS and the main inducer of pro-inflammatory responses to LPS <ref>{{Cite journal |last=Park |first=Beom Seok |last2=Song |first2=Dong Hyun |last3=Kim |first3=Ho Min |last4=Choi |first4=Byong-Seok |last5=Lee |first5=Hayyoung |last6=Lee |first6=Jie-Oh |date=2009-04 |title=The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex |url=https://www.nature.com/articles/nature07830 |journal=Nature |language=en |volume=458 |issue=7242 |pages=1191–1195 |doi=10.1038/nature07830 |issn=0028-0836}}</ref><ref>{{Cite journal |last=Park |first=Beom Seok |last2=Lee |first2=Jie-Oh |date=2013-12-06 |title=Recognition of lipopolysaccharide pattern by TLR4 complexes |url=https://www.nature.com/articles/emm201397 |journal=Experimental & Molecular Medicine |language=en |volume=45 |issue=12 |pages=e66–e66 |doi=10.1038/emm.2013.97 |issn=2092-6413 |pmc=PMC3880462 |pmid=24310172}}</ref>.
-TLR4 signaling responds to signals by forming a complex using an extracellular [[Leucine-rich repeat|leucine-rich repeat domain]] (LRR) and an intracellular [[Toll-Interleukin receptor|toll/interleukin-1 receptor]] (TIR) domain. LPS stimulation induces a series of interactions with several accessory proteins which form the TLR4 complex on the cell surface. LPS recognition is initiated by an LPS binding to an [[Lipopolysaccharide binding protein|LBP protein]]. This LPS-LBP complex transfers the LPS to [[CD14]]. [[CD14]] is a glycosylphosphatidylinositol-anchored membrane protein that binds the LPS-LBP complex and facilitates the transfer of LPS to [[Lymphocyte antigen 96|MD-2 protein]], which is associated with the extracellular domain of TLR4. LPS binding promotes the dimerization of TLR4/MD-2. The conformational changes of the TLR4 induce the recruitment of intracellular adaptor proteins containing the TIR domain which is necessary to activate the downstream signaling pathway.<ref name="Lu_2008">{{cite journal | vauthors = Lu YC, Yeh WC, Ohashi PS | title = LPS/TLR4 signal transduction pathway | journal = Cytokine | volume = 42 | issue = 2 | pages = 145–151 | date = May 2008 | pmid = 18304834 | doi = 10.1016/j.cyto.2008.01.006 }}</ref>
+TLR4 activation and response to LPS is greatly influenced by the polysaccharide domain and the molecular structure of Lipid A moiety of the LPS molecules. Hexa-acylated and diphosphorylated LPS, like Escherichia coli LPS (O111:B4), is one of the most potent agonists of TLR4 whereas under-acylated LPS and dephosphorylated LPS species have a weaker pro-inflammatory activity especially in human cells <ref>{{Cite journal |last=Steimle |first=Alex |last2=Autenrieth |first2=Ingo B. |last3=Frick |first3=Julia-Stefanie |date=2016-08 |title=Structure and function: Lipid A modifications in commensals and pathogens |url=https://pubmed.ncbi.nlm.nih.gov/27009633/ |journal=International journal of medical microbiology: IJMM |volume=306 |issue=5 |pages=290–301 |doi=10.1016/j.ijmm.2016.03.001 |issn=1618-0607 |pmid=27009633}}</ref>. Structural determinants of this phenomenon are found in the TLR4/MD-2 complex and also in CD14 protein <ref>{{Cite journal |last=Park |first=Beom Seok |last2=Song |first2=Dong Hyun |last3=Kim |first3=Ho Min |last4=Choi |first4=Byong-Seok |last5=Lee |first5=Hayyoung |last6=Lee |first6=Jie-Oh |date=2009-04 |title=The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex |url=https://www.nature.com/articles/nature07830 |journal=Nature |language=en |volume=458 |issue=7242 |pages=1191–1195 |doi=10.1038/nature07830 |issn=0028-0836}}</ref><ref>{{Cite journal |last=Kelley |first=Stacy L. |last2=Lukk |first2=Tiit |last3=Nair |first3=Satish K. |last4=Tapping |first4=Richard I. |date=2013-02-01 |title=The Crystal Structure of Human Soluble CD14 Reveals a Bent Solenoid with a Hydrophobic Amino-Terminal Pocket |url=https://journals.aai.org/jimmunol/article/190/3/1304/86915/The-Crystal-Structure-of-Human-Soluble-CD14 |journal=The Journal of Immunology |language=en |volume=190 |issue=3 |pages=1304–1311 |doi=10.4049/jimmunol.1202446 |issn=0022-1767 |pmc=PMC3552104 |pmid=23264655}}</ref>. The polysaccharide portion covalently bound to lipid A plays also and indispensable role in TLR4 activation through CD14/TLR4/MD-2 <ref>{{Cite journal |last=Muroi |first=Masashi |last2=Tanamoto |first2=Ken-Ichi |date=2002-11 |title=The polysaccharide portion plays an indispensable role in Salmonella lipopolysaccharide-induced activation of NF-kappaB through human toll-like receptor 4 |url=https://pubmed.ncbi.nlm.nih.gov/12379680/ |journal=Infection and Immunity |volume=70 |issue=11 |pages=6043–6047 |doi=10.1128/IAI.70.11.6043-6047.2002 |issn=0019-9567 |pmid=12379680}}</ref>. However, It was demonstrated that the lipid A moiety alone was less active than the full LPS molecule <ref>{{Cite journal |last=Cavaillon |first=J M |last2=Fitting |first2=C |last3=Caroff |first3=M |last4=Haeffner-Cavaillon |first4=N |date=1989-03 |title=Dissociation of cell-associated interleukin-1 (IL-1) and IL-1 release induced by lipopolysaccharide and lipid A |url=https://journals.asm.org/doi/10.1128/iai.57.3.791-797.1989 |journal=Infection and Immunity |language=en |volume=57 |issue=3 |pages=791–797 |doi=10.1128/iai.57.3.791-797.1989 |issn=0019-9567 |pmc=PMC313178 |pmid=2537258}}</ref>.
-Several transcript variants of this gene have been found, but the protein-coding potential of most of them is uncertain.<ref>{{cite web | title = Entrez Gene: TLR4 toll-like receptor 4| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7099}}</ref>
+== Signaling ==
+Unlike all the other TLRs, TLR4 stimulation triggers two signaling pathways called the [[MYD88|MyD88]]-dependent and the [[TICAM1|TRIF]]-dependent one after the adaptor proteins involved in their induction <ref>{{Cite journal |last=Shen |first=Hua |last2=Tesar |first2=Bethany M. |last3=Walker |first3=Wendy E. |last4=Goldstein |first4=Daniel R. |date=2008-08-01 |title=Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation |url=https://pubmed.ncbi.nlm.nih.gov/18641322/ |journal=Journal of Immunology (Baltimore, Md.: 1950) |volume=181 |issue=3 |pages=1849–1858 |doi=10.4049/jimmunol.181.3.1849 |issn=1550-6606 |pmc=2507878 |pmid=18641322}}</ref><ref>{{Cite journal |last=Shen |first=Hua |last2=Tesar |first2=Bethany M. |last3=Walker |first3=Wendy E. |last4=Goldstein |first4=Daniel R. |date=2008-08-01 |title=Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation |url=https://pubmed.ncbi.nlm.nih.gov/18641322/ |journal=Journal of Immunology (Baltimore, Md.: 1950) |volume=181 |issue=3 |pages=1849–1858 |doi=10.4049/jimmunol.181.3.1849 |issn=1550-6606 |pmc=2507878 |pmid=18641322}}</ref>. The MyD88-dependent signaling is triggered by TLR4 localized to the plasma membrane, while the TRIF-dependent one by the TLR4 internalized in endosomes.
-Most of the reported effects of TLR4 signaling in tumors are pro-carcinogenic mainly due to contributions of proinflammatory cytokine signaling (whose expression is driven by TLR-mediated signals) to tumor-promoting microenvironment.<ref name="sciencedirect.com">{{cite journal | vauthors = Korneev KV, Atretkhany KN, Drutskaya MS, Grivennikov SI, Kuprash DV, Nedospasov SA | title = TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis | journal = Cytokine | volume = 89 | pages = 127–135 | date = January 2017 | pmid = 26854213 | doi = 10.1016/j.cyto.2016.01.021 }}</ref>
+These signaling pathways lead to the production of two sets of cytokines. The MyD88-dependent pathway induces the production of pro-inflammatory cytokines while TRIF-dependent pathway induces the production of type I interferons and chemokines. The molecular structure of TLR4 ligands (LPS or DAMPs), as well as their complexation with proteins or lipids, greatly influence the action of these TLR4-related signaling pathways, leading to different cytokine balances.[[File:Toll-like receptor pathways revised.jpg|thumbnail|416x416px|MyD88 and TRIF signaling pathway of toll-like receptor 4.]]
-== Signaling ==
-Upon LPS recognition, conformational changes in the TLR4 receptors result in recruitment of intracellular TIR-domains containing adaptor molecules. These adaptors are associated with the TLR4 cluster via homophilic interactions between the TIR domains. There are four adaptor proteins involved in two major intracellular signaling pathways.<ref name="O'Neill _2013">{{cite journal | vauthors = O'Neill LA, Golenbock D, Bowie AG | title = The history of Toll-like receptors - redefining innate immunity | journal = Nature Reviews. Immunology | volume = 13 | issue = 6 | pages = 453–460 | date = June 2013 | pmid = 23681101 | doi = 10.1038/nri3446 | hdl-access = free | s2cid = 205491986 | hdl = 2262/72552 }}</ref>
-[[File:Toll-like receptor pathways revised.jpg|thumbnail|416x416px|Signaling pathway of toll-like receptor 4. Dashed grey lines represent unknown associations]]
 === MyD88 – dependent pathway ===
-The MyD88-dependent pathway is regulated by two adaptor-associated proteins: Myeloid Differentiation Primary Response Gene 88 ([[MYD88|MyD88]]) and TIR Domain-Containing Adaptor Protein ([[TIRAP]]). TIRAP-MyD88 regulates early [[NF-κB|NF-κβ]] activation and production of [[proinflammatory cytokine]]s, such as [[Interleukin 12|IL-12]].<ref name="pmid25071777" /> MyD88 signaling involves the activation of IL-1 Receptor-Associated Kinases ([[Interleukin-1 receptor-associated kinase|IRAKs]]) and the adaptor molecules TNF Receptor-Associated Factor 6 ([[TRAF6]]). TRAF6 induces the activation of [[MAP3K7|TAK1]] (Transforming growth factor-β-Activated Kinase 1) that leads to the activation of [[MAPK/ERK pathway|MAPK cascades]] (Mitogen-Activated Protein Kinase) and [[IκB kinase|IKK]] (IκB Kinase). IKKs' signaling pathway leads to the induction of the transcription factor [[NF-κB]], while activation of MAPK cascades lead to the activation of another transcription factor [[AP-1 transcription factor|AP-1]]. Both of them have a role in the expression of proinflammatory cytokines.<ref name="Lu_2008" /> The activation of NF-κB via TAK-1 is complex, and it starts by the assembly of a protein complex called the [[COP9 signalosome complex subunit 3|signalosome]], which is made of a scaffolding protein, called [[IKBKG|NEMO]]. The protein complex is made from two different κB kinases, called IKKα and IKKβ. This causes the addition of a small regulatory protein to the signalosome called [[ubiquitin]], that acts to initiate the release of the NF-κB protein, which coordinates translocation in the nucleus of cytokines.<ref name="Pålsson-McDermott_2004">{{cite journal | vauthors = Pålsson-McDermott EM, O'Neill LA | title = Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4 | journal = Immunology | volume = 113 | issue = 2 | pages = 153–162 | date = October 2004 | pmid = 15379975 | pmc = 1782563 | doi = 10.1111/j.1365-2567.2004.01976.x }}</ref>
+The MyD88-dependent pathway is regulated by two adaptor-associated proteins: Myeloid Differentiation Primary Response Gene 88 ([[MYD88|MyD88]]) and TIR Domain-Containing Adaptor Protein ([[TIRAP]]). TIRAP-MyD88 regulates early [[NF-κB|NF-κβ]] activation and production of [[proinflammatory cytokine]]s, such as [[Interleukin 12|IL-12]].<ref name="pmid25071777" /> MyD88 signaling involves the activation of IL-1 Receptor-Associated Kinases ([[Interleukin-1 receptor-associated kinase|IRAKs]]) and the adaptor molecules TNF Receptor-Associated Factor 6 ([[TRAF6]]). TRAF6 induces the activation of [[MAP3K7|TAK1]] (Transforming growth factor-β-Activated Kinase 1) that leads to the activation of [[MAPK/ERK pathway|MAPK cascades]] (Mitogen-Activated Protein Kinase) and [[IκB kinase|IKK]] (IκB Kinase). IKKs' signaling pathway leads to the induction of the transcription factor [[NF-κB]], while activation of MAPK cascades lead to the activation of another transcription factor [[AP-1 transcription factor|AP-1]]. Both of them have a role in the expression of proinflammatory cytokines.<ref name="Lu_2008">{{cite journal |vauthors=Lu YC, Yeh WC, Ohashi PS |date=May 2008 |title=LPS/TLR4 signal transduction pathway |journal=Cytokine |volume=42 |issue=2 |pages=145–151 |doi=10.1016/j.cyto.2008.01.006 |pmid=18304834}}</ref> The activation of NF-κB via TAK-1 is complex, and it starts by the assembly of a protein complex called the [[COP9 signalosome complex subunit 3|signalosome]], which is made of a scaffolding protein, called [[IKBKG|NEMO]]. The protein complex is made from two different κB kinases, called IKKα and IKKβ. This causes the addition of a small regulatory protein to the signalosome called [[ubiquitin]], that acts to initiate the release of the NF-κB protein, which coordinates translocation in the nucleus of cytokines.<ref name="Pålsson-McDermott_2004">{{cite journal | vauthors = Pålsson-McDermott EM, O'Neill LA | title = Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4 | journal = Immunology | volume = 113 | issue = 2 | pages = 153–162 | date = October 2004 | pmid = 15379975 | pmc = 1782563 | doi = 10.1111/j.1365-2567.2004.01976.x }}</ref>  Collectively, the MyD88-dependent signaling pathway induces the expression of genes encoding pro-inflammatory mediators, such as tumor necrosis factor α (TNF-α), interleukin (IL)-6, and type III interferons (IFNλ1/2) and participates in the production of anti-inflammatory mediators, like IL-10 helping to terminate the inflammation <ref>{{Cite journal |last=Meissner |first=Felix |last2=Scheltema |first2=Richard A. |last3=Mollenkopf |first3=Hans-Joachim |last4=Mann |first4=Matthias |date=2013-04-26 |title=Direct Proteomic Quantification of the Secretome of Activated Immune Cells |url=https://www.science.org/doi/10.1126/science.1232578 |journal=Science |language=en |volume=340 |issue=6131 |pages=475–478 |doi=10.1126/science.1232578 |issn=0036-8075}}</ref><ref>{{Cite journal |last=Kawai |first=Taro |last2=Takeuchi |first2=Osamu |last3=Fujita |first3=Takashi |last4=Inoue |first4=Jun-ichiro |last5=Mühlradt |first5=Peter F. |last6=Sato |first6=Shintaro |last7=Hoshino |first7=Katsuaki |last8=Akira |first8=Shizuo |date=2001-11-15 |title=Lipopolysaccharide Stimulates the MyD88-Independent Pathway and Results in Activation of IFN-Regulatory Factor 3 and the Expression of a Subset of Lipopolysaccharide-Inducible Genes |url=https://doi.org/10.4049/jimmunol.167.10.5887 |journal=The Journal of Immunology |volume=167 |issue=10 |pages=5887–5894 |doi=10.4049/jimmunol.167.10.5887 |issn=0022-1767}}</ref><ref>{{Cite journal |last=Chanteux |first=Hugues |last2=Guisset |first2=Amélie C. |last3=Pilette |first3=Charles |last4=Sibille |first4=Yves |date=2007-10-04 |title=LPS induces IL-10 production by human alveolar macrophages via MAPKinases- and Sp1-dependent mechanisms |url=https://doi.org/10.1186/1465-9921-8-71 |journal=Respiratory Research |volume=8 |issue=1 |pages=71 |doi=10.1186/1465-9921-8-71 |issn=1465-993X |pmc=PMC2080632 |pmid=17916230}}</ref>.
-=== MyD88 – independent pathway ===
+=== TRIF – dependent pathway ===
+The TRIF-dependent pathway involves the internalization of TLR4 in endosomes and the recruitment of the adaptor proteins TIR-domain-containing adaptor inducing interferon-β ([[TRIF]]) and TRIF-related Adaptor Molecule (TRAM). TRAM-TRIF signals activate the ubiquitin ligase TRAF3 followed by the activation of non-canonical IKK kinases: TANK binding kinase 1 (TBK1) and IKKε. TBK1 phosphorylates the pLxIS consensus motif of TRIF that is necessary to recruit interferon regulatory factor (IRF) 3. [[IRF3]] is also phosphorylated by TBK1 and then dissociates from TRIF, dimerizes and translocates to the nucleus <ref>{{Cite journal |last=Ciesielska |first=Anna |last2=Matyjek |first2=Marta |last3=Kwiatkowska |first3=Katarzyna |date=2020-10-15 |title=TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904555/ |journal=Cellular and Molecular Life Sciences |language=en |volume=78 |issue=4 |pages=1233–1261 |doi=10.1007/s00018-020-03656-y |issn=1420-682X}}</ref>. Finally, IRF3 induces the expression of genes encoding type I IFN, the chemokine CCL5/ RANTES and interferon-regulated genes as that encoding the chemokine CXCL10/IP-10 <ref>{{Cite journal |last=Meissner |first=Felix |last2=Scheltema |first2=Richard A. |last3=Mollenkopf |first3=Hans-Joachim |last4=Mann |first4=Matthias |date=2013-04-26 |title=Direct Proteomic Quantification of the Secretome of Activated Immune Cells |url=https://www.science.org/doi/10.1126/science.1232578 |journal=Science |language=en |volume=340 |issue=6131 |pages=475–478 |doi=10.1126/science.1232578 |issn=0036-8075}}</ref><ref>{{Cite journal |last=Kawai |first=Taro |last2=Takeuchi |first2=Osamu |last3=Fujita |first3=Takashi |last4=Inoue |first4=Jun-ichiro |last5=Mühlradt |first5=Peter F. |last6=Sato |first6=Shintaro |last7=Hoshino |first7=Katsuaki |last8=Akira |first8=Shizuo |date=2001-11-15 |title=Lipopolysaccharide Stimulates the MyD88-Independent Pathway and Results in Activation of IFN-Regulatory Factor 3 and the Expression of a Subset of Lipopolysaccharide-Inducible Genes |url=https://doi.org/10.4049/jimmunol.167.10.5887 |journal=The Journal of Immunology |volume=167 |issue=10 |pages=5887–5894 |doi=10.4049/jimmunol.167.10.5887 |issn=0022-1767}}</ref><ref>{{Cite journal |last=Chanteux |first=Hugues |last2=Guisset |first2=Amélie C. |last3=Pilette |first3=Charles |last4=Sibille |first4=Yves |date=2007-10-04 |title=LPS induces IL-10 production by human alveolar macrophages via MAPKinases- and Sp1-dependent mechanisms |url=https://doi.org/10.1186/1465-9921-8-71 |journal=Respiratory Research |volume=8 |issue=1 |pages=71 |doi=10.1186/1465-9921-8-71 |issn=1465-993X |pmc=PMC2080632 |pmid=17916230}}</ref><ref name="O'Neill _2013">{{cite journal |vauthors=O'Neill LA, Golenbock D, Bowie AG |date=June 2013 |title=The history of Toll-like receptors - redefining innate immunity |journal=Nature Reviews. Immunology |volume=13 |issue=6 |pages=453–460 |doi=10.1038/nri3446 |pmid=23681101 |s2cid=205491986 |hdl-access=free |hdl=2262/72552}}</ref>.
-This TRIF-dependent pathway involves the recruitment of the adaptor proteins TIR-domain-containing adaptor inducing interferon-β ([[TRIF]]) and TRIF-related Adaptor Molecule (TRAM). TRAM-TRIF signals activate the transcription factor Interferon Regulatory Factor-3 ([[IRF3]]) via [[TRAF3]]. IRF3 activation induces the production of [[Interferon type I|type 1 interferons]].<ref name="O'Neill _2013" />
+== Immune cell activation ==
-=== SARM – TRIF-mediated pathway ===
+TLR4 activation by LPS on innate immune cells such as macrophages and DC induces the secretion of both pro-inflammatory and type I interferon cytokines and chemokines. It also induces the stimulation of antigen presentation and upregulation of costimulatory molecules such as [[CD40 (protein)|CD40]], [[CD80]] and [[CD86]] on the cell surface which are required for antigen presentation for T lymphocytes <ref>{{Cite journal |last=Lien |first=E. |last2=Means |first2=T. K. |last3=Heine |first3=H. |last4=Yoshimura |first4=A. |last5=Kusumoto |first5=S. |last6=Fukase |first6=K. |last7=Fenton |first7=M. J. |last8=Oikawa |first8=M. |last9=Qureshi |first9=N. |last10=Monks |first10=B. |last11=Finberg |first11=R. W. |last12=Ingalls |first12=R. R. |last13=Golenbock |first13=D. T. |date=2000-02 |title=Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide |url=https://pubmed.ncbi.nlm.nih.gov/10683379/ |journal=The Journal of Clinical Investigation |volume=105 |issue=4 |pages=497–504 |doi=10.1172/JCI8541 |issn=0021-9738 |pmid=10683379}}</ref><ref>{{Cite journal |last=Shetab Boushehri |first=Maryam A. |last2=Lamprecht |first2=Alf |date=2018-11-05 |title=TLR4-Based Immunotherapeutics in Cancer: A Review of the Achievements and Shortcomings |url=https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.8b00691 |journal=Molecular Pharmaceutics |language=en |volume=15 |issue=11 |pages=4777–4800 |doi=10.1021/acs.molpharmaceut.8b00691 |issn=1543-8384}}</ref>. So, in addition to innate immune cell stimulation, activation of TLR4 by LPS enables the onset, the recruitment, the polarization and the maintenance of effective and long-lasting T-cell responses <ref>{{Cite journal |last=Shetab Boushehri |first=Maryam A. |last2=Lamprecht |first2=Alf |date=2018-11-05 |title=TLR4-Based Immunotherapeutics in Cancer: A Review of the Achievements and Shortcomings |url=https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.8b00691 |journal=Molecular Pharmaceutics |language=en |volume=15 |issue=11 |pages=4777–4800 |doi=10.1021/acs.molpharmaceut.8b00691 |issn=1543-8384}}</ref><ref>{{Cite journal |last=Shen |first=Hua |last2=Tesar |first2=Bethany M. |last3=Walker |first3=Wendy E. |last4=Goldstein |first4=Daniel R. |date=2008-08-01 |title=Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation |url=https://pubmed.ncbi.nlm.nih.gov/18641322/ |journal=Journal of Immunology (Baltimore, Md.: 1950) |volume=181 |issue=3 |pages=1849–1858 |doi=10.4049/jimmunol.181.3.1849 |issn=1550-6606 |pmc=2507878 |pmid=18641322}}</ref>. However, significant differences were found in the signaling pathways leading to this phenomenon. In macrophages, the upregulation depends strictly on the TRIF-dependent pathway, whereas in DC both the MyD88- and TRIF-dependent ones are involved <ref>{{Cite journal |last=Kaisho |first=T. |last2=Takeuchi |first2=O. |last3=Kawai |first3=T. |last4=Hoshino |first4=K. |last5=Akira |first5=S. |date=2001-05-01 |title=Endotoxin-induced maturation of MyD88-deficient dendritic cells |url=https://pubmed.ncbi.nlm.nih.gov/11313410/ |journal=Journal of Immunology (Baltimore, Md.: 1950) |volume=166 |issue=9 |pages=5688–5694 |doi=10.4049/jimmunol.166.9.5688 |issn=0022-1767 |pmid=11313410}}</ref><ref>{{Cite journal |last=Hoebe |first=Kasper |last2=Janssen |first2=Edith M. |last3=Kim |first3=Sung O. |last4=Alexopoulou |first4=Lena |last5=Flavell |first5=Richard A. |last6=Han |first6=Jiahuai |last7=Beutler |first7=Bruce |date=2003-12 |title=Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways |url=https://www.nature.com/articles/ni1010 |journal=Nature Immunology |language=en |volume=4 |issue=12 |pages=1223–1229 |doi=10.1038/ni1010 |issn=1529-2916}}</ref><ref>{{Cite journal |last=Shen |first=Hua |last2=Tesar |first2=Bethany M. |last3=Walker |first3=Wendy E. |last4=Goldstein |first4=Daniel R. |date=2008-08-01 |title=Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation |url=https://pubmed.ncbi.nlm.nih.gov/18641322/ |journal=Journal of Immunology (Baltimore, Md.: 1950) |volume=181 |issue=3 |pages=1849–1858 |doi=10.4049/jimmunol.181.3.1849 |issn=1550-6606 |pmc=2507878 |pmid=18641322}}</ref><ref>{{Cite journal |last=Trombetta |first=E. Sergio |last2=Ebersold |first2=Melanie |last3=Garrett |first3=Wendy |last4=Pypaert |first4=Marc |last5=Mellman |first5=Ira |date=2003-02-28 |title=Activation of Lysosomal Function During Dendritic Cell Maturation |url=https://www.science.org/doi/10.1126/science.1080106 |journal=Science |language=en |volume=299 |issue=5611 |pages=1400–1403 |doi=10.1126/science.1080106 |issn=0036-8075}}</ref>. The increased cell surface presence of the costimulatory molecules and also of MHC II is a hallmark of DC maturation required for antigen presentation by these cells <ref>{{Cite journal |last=Turley |first=Shannon J. |last2=Inaba |first2=Kayo |last3=Garrett |first3=Wendy S. |last4=Ebersold |first4=Melanie |last5=Unternaehrer |first5=Julia |last6=Steinman |first6=Ralph M. |last7=Mellman |first7=Ira |date=2000-04-21 |title=Transport of Peptide-MHC Class II Complexes in Developing Dendritic Cells |url=https://www.science.org/doi/10.1126/science.288.5465.522 |journal=Science |language=en |volume=288 |issue=5465 |pages=522–527 |doi=10.1126/science.288.5465.522 |issn=0036-8075}}</ref>. Beside the contribution to the upregulation of MHC II and costimulatory molecules, the TLR4-triggered MyD88-dependent signaling in DC also induces production of cytokines leading to Th1 cell polarization and also facilitates fusion of MHC I-bearing recycling endosomes with phagosomes to allow cross-presentation of antigens during infection <ref>{{Cite journal |last=Nair-Gupta |first=Priyanka |last2=Baccarini |first2=Alessia |last3=Tung |first3=Navpreet |last4=Seyffer |first4=Fabian |last5=Florey |first5=Oliver |last6=Huang |first6=Yunjie |last7=Banerjee |first7=Meenakshi |last8=Overholtzer |first8=Michael |last9=Roche |first9=Paul A. |last10=Tampé |first10=Robert |last11=Brown |first11=Brian D. |last12=Amsen |first12=Derk |last13=Whiteheart |first13=Sidney W. |last14=Blander |first14=J. Magarian |date=2014-07 |title=TLR Signals Induce Phagosomal MHC-I Delivery from the Endosomal Recycling Compartment to Allow Cross-Presentation |url=https://doi.org/10.1016/j.cell.2014.04.054 |journal=Cell |volume=158 |issue=3 |pages=506–521 |doi=10.1016/j.cell.2014.04.054 |issn=0092-8674 |pmc=PMC4212008 |pmid=25083866}}</ref>.
+The impact of TLR4 activation on the innate and adaptive immune system explains why TLR4 agonists, such as LPS derivatives, have been developed as vaccine adjuvants. Among them is monophosphoryl lipid A (MPL), a detoxified LPS, which has been approved as a vaccine adjuvant in five human vaccines <ref>{{Cite journal |last=Paavonen |first=Jorma |last2=Jenkins |first2=David |last3=Bosch |first3=F. Xavier |last4=Naud |first4=Paulo |last5=Salmerón |first5=Jorge |last6=Wheeler |first6=Cosette M. |last7=Chow |first7=Song-Nan |last8=Apter |first8=Dan L. |last9=Kitchener |first9=Henry C. |last10=Castellsague |first10=Xavier |last11=de Carvalho |first11=Newton S. |last12=Skinner |first12=S. Rachel |last13=Harper |first13=Diane M. |last14=Hedrick |first14=James A. |last15=Jaisamrarn |first15=Unnop |date=2007-06-30 |title=Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial |url=https://pubmed.ncbi.nlm.nih.gov/17602732/ |journal=Lancet (London, England) |volume=369 |issue=9580 |pages=2161–2170 |doi=10.1016/S0140-6736(07)60946-5 |issn=1474-547X |pmid=17602732}}</ref><ref>{{Cite journal |last=Kundi |first=Michael |date=2007-04 |title=New hepatitis B vaccine formulated with an improved adjuvant system |url=https://pubmed.ncbi.nlm.nih.gov/17408363/ |journal=Expert Review of Vaccines |volume=6 |issue=2 |pages=133–140 |doi=10.1586/14760584.6.2.133 |issn=1744-8395 |pmid=17408363}}</ref><ref>{{Cite journal |last=Garçon |first=Nathalie |last2=Di Pasquale |first2=Alberta |date=2017-01-02 |title=From discovery to licensure, the Adjuvant System story |url=https://www.tandfonline.com/doi/full/10.1080/21645515.2016.1225635 |journal=Human Vaccines & Immunotherapeutics |language=en |volume=13 |issue=1 |pages=19–33 |doi=10.1080/21645515.2016.1225635 |issn=2164-5515 |pmc=PMC5287309 |pmid=27636098}}</ref>.
-A fifth TIR-domain-containing adaptor protein called Sterile α and HEAT (Armadillo motif) (SARM) is a TLR4 signaling pathway inhibitor. SARM activation by LPS-binding inhibits -TRIF-mediated pathways but does not inhibit MyD88-mediated pathways. This mechanism prevents an excessive activation in response to LPS which may lead to inflammation-induced damage such as [[sepsis]].<ref name="Lu_2008" />
-== Evolutionary history ==
+== Evolutionary history and polymorphism ==
-TLR4 originated when TLR2 and TLR4 diverged about 500 million years ago near the beginning of vertebrate evolution.<ref>{{cite book | vauthors = Beutler B, Rehli M | title = Toll-Like Receptor Family Members and Their Ligands | chapter = Evolution of the TIR, Tolls and TLRS: Functional Inferences from Computational Biology | series = Current Topics in Microbiology and Immunology | volume = 270 | pages = 1–21 | year = 2002 | pmid = 12467241 | doi = 10.1007/978-3-642-59430-4_1 | isbn = 978-3-642-63975-3 }}</ref> Sequence alignments of human and great ape TLR4 exons have demonstrated that not much evolution has occurred in human TLR4 since our divergence from our last common ancestor with chimpanzees; human and chimp TLR4 exons only differ by three substitutions while humans and baboons are 93.5% similar in the extracellular domain.<ref>{{cite journal | vauthors = Smirnova I, Poltorak A, Chan EK, McBride C, Beutler B | title = Phylogenetic variation and polymorphism at the toll-like receptor 4 locus (TLR4) | journal = Genome Biology | volume = 1 | issue = 1 | pages = RESEARCH002 | year = 2000 | pmid = 11104518 | pmc = 31919 | doi = 10.1186/gb-2000-1-1-research002 | doi-access = free }}</ref> Notably, humans possess a greater number of early stop codons in TLR4 than great apes; in a study of 158 humans worldwide, 0.6% had a nonsense mutation.<ref>{{cite journal | vauthors = Quach H, Wilson D, Laval G, Patin E, Manry J, Guibert J, Barreiro LB, Nerrienet E, Verschoor E, Gessain A, Przeworski M, Quintana-Murci L | display-authors = 6 | title = Different selective pressures shape the evolution of Toll-like receptors in human and African great ape populations | journal = Human Molecular Genetics | volume = 22 | issue = 23 | pages = 4829–4840 | date = December 2013 | pmid = 23851028 | pmc = 3820138 | doi = 10.1093/hmg/ddt335 }}</ref><ref name="Barreiro_2009">{{cite journal | vauthors = Barreiro LB, Ben-Ali M, Quach H, Laval G, Patin E, Pickrell JK, Bouchier C, Tichit M, Neyrolles O, Gicquel B, Kidd JR, Kidd KK, Alcaïs A, Ragimbeau J, Pellegrini S, Abel L, Casanova JL, Quintana-Murci L | display-authors = 6 | title = Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense | journal = PLOS Genetics | volume = 5 | issue = 7 | pages = e1000562 | date = July 2009 | pmid = 19609346 | pmc = 2702086 | doi = 10.1371/journal.pgen.1000562 | doi-access = free }}</ref> This suggests that there are weaker evolutionary pressures on the human TLR4 than on our primate relatives. The distribution of human TLR4 polymorphisms matches the out-of-Africa migration, and it is likely that the polymorphisms were generated in Africa before migration to other continents.<ref name="Barreiro_2009" /><ref>{{cite journal | vauthors = Plantinga TS, Ioana M, Alonso S, Izagirre N, Hervella M, Joosten LA, van der Meer JW, de la Rúa C, Netea MG | display-authors = 6 | title = The evolutionary history of TLR4 polymorphisms in Europe | journal = Journal of Innate Immunity | volume = 4 | issue = 2 | pages = 168–175 | year = 2012 | pmid = 21968286 | pmc = 6741577 | doi = 10.1159/000329492 }}</ref>
+TLR4 originated when TLR2 and TLR4 diverged about 500 million years ago near the beginning of vertebrate evolution.<ref>{{cite book | vauthors = Beutler B, Rehli M | title = Toll-Like Receptor Family Members and Their Ligands | chapter = Evolution of the TIR, Tolls and TLRS: Functional Inferences from Computational Biology | series = Current Topics in Microbiology and Immunology | volume = 270 | pages = 1–21 | year = 2002 | pmid = 12467241 | doi = 10.1007/978-3-642-59430-4_1 | isbn = 978-3-642-63975-3 }}</ref> Sequence alignments of human and great ape TLR4 exons have demonstrated that not much evolution has occurred in human TLR4 since our divergence from our last common ancestor with chimpanzees; human and chimp TLR4 exons only differ by three substitutions while humans and baboons are 93.5% similar in the extracellular domain <ref>{{cite journal | vauthors = Smirnova I, Poltorak A, Chan EK, McBride C, Beutler B | title = Phylogenetic variation and polymorphism at the toll-like receptor 4 locus (TLR4) | journal = Genome Biology | volume = 1 | issue = 1 | pages = RESEARCH002 | year = 2000 | pmid = 11104518 | pmc = 31919 | doi = 10.1186/gb-2000-1-1-research002 | doi-access = free }}</ref>. Notably, humans possess a greater number of early stop codons in TLR4 than great apes; in a study of 158 humans worldwide, 0.6% had a nonsense mutation <ref>{{cite journal | vauthors = Quach H, Wilson D, Laval G, Patin E, Manry J, Guibert J, Barreiro LB, Nerrienet E, Verschoor E, Gessain A, Przeworski M, Quintana-Murci L | display-authors = 6 | title = Different selective pressures shape the evolution of Toll-like receptors in human and African great ape populations | journal = Human Molecular Genetics | volume = 22 | issue = 23 | pages = 4829–4840 | date = December 2013 | pmid = 23851028 | pmc = 3820138 | doi = 10.1093/hmg/ddt335 }}</ref><ref name="Barreiro_2009">{{cite journal | vauthors = Barreiro LB, Ben-Ali M, Quach H, Laval G, Patin E, Pickrell JK, Bouchier C, Tichit M, Neyrolles O, Gicquel B, Kidd JR, Kidd KK, Alcaïs A, Ragimbeau J, Pellegrini S, Abel L, Casanova JL, Quintana-Murci L | display-authors = 6 | title = Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense | journal = PLOS Genetics | volume = 5 | issue = 7 | pages = e1000562 | date = July 2009 | pmid = 19609346 | pmc = 2702086 | doi = 10.1371/journal.pgen.1000562 | doi-access = free }}</ref>. This suggests that there are weaker evolutionary pressures on the human TLR4 than on our primate relatives. The distribution of human TLR4 polymorphisms matches the out-of-Africa migration, and it is likely that the polymorphisms were generated in Africa before migration to other continents <ref name="Barreiro_2009" /><ref>{{cite journal | vauthors = Plantinga TS, Ioana M, Alonso S, Izagirre N, Hervella M, Joosten LA, van der Meer JW, de la Rúa C, Netea MG | display-authors = 6 | title = The evolutionary history of TLR4 polymorphisms in Europe | journal = Journal of Innate Immunity | volume = 4 | issue = 2 | pages = 168–175 | year = 2012 | pmid = 21968286 | pmc = 6741577 | doi = 10.1159/000329492 }}</ref>.
+Various single nucleotide polymorphisms (SNPs) of TLR4 have been identified in humans . For some of them, an association with increased susceptibility to Gram-negative bacterial infections or faster progression and a more severe course of sepsis in critically ill patients was reported.However, they are very rare, and their frequency varies according to ethnic origin. The 2 predominant SNPs are Asp299Gly and Thr399Ile, with a frequency of <10% in the Caucasian population and even lower in the Asian population <ref>{{Cite journal |last=Noreen |first=Mamoona |last2=Shah |first2=Muhammad Ali A. |last3=Mall |first3=Sheeba Murad |last4=Choudhary |first4=Shazia |last5=Hussain |first5=Tahir |last6=Ahmed |first6=Iltaf |last7=Jalil |first7=Syed Fazal |last8=Raza |first8=Muhammad Imran |date=2012-03 |title=TLR4 polymorphisms and disease susceptibility |url=https://pubmed.ncbi.nlm.nih.gov/22277994/ |journal=Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.] |volume=61 |issue=3 |pages=177–188 |doi=10.1007/s00011-011-0427-1 |issn=1420-908X |pmid=22277994}}</ref>. These two SNPs are missense mutations, thus associated with a loss of function, which may explain their negative impact on infection control. Studies have indeed shown that TLR4 D299G SNP limits the response to LPS by compromising MyD88 and TRIF recruitment to TLR4, and thus cytokine secretion, but without affecting TLR4 expression <ref>{{Cite journal |last=Long |first=Huaicong |last2=O'Connor |first2=Brian P. |last3=Zemans |first3=Rachel L. |last4=Zhou |first4=Xiaofang |last5=Yang |first5=Ivana V. |last6=Schwartz |first6=David A. |date=2014-04-02 |title=The Toll-Like Receptor 4 Polymorphism Asp299Gly but Not Thr399Ile Influences TLR4 Signaling and Function |url=https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093550 |journal=PLOS ONE |language=en |volume=9 |issue=4 |pages=e93550 |doi=10.1371/journal.pone.0093550 |issn=1932-6203 |pmc=PMC3973565 |pmid=24695807}}</ref><ref>{{Cite web |url=https://journals.aai.org/jimmunol/article/188/9/4506/39640 |access-date=2024-02-20 |website=journals.aai.org}}</ref>. Structural analyses of human TLR4 with SNP D299G suggest that this amino acid change affects van der Waals interaction and hydrogen bonding in leucine-rich repeats, modulating its surface properties which may affect LPS ligand binding to TLR4 <ref>{{Cite journal |last=Ohto |first=Umeharu |last2=Yamakawa |first2=Natsuko |last3=Akashi-Takamura |first3=Sachiko |last4=Miyake |first4=Kensuke |last5=Shimizu |first5=Toshiyuki |date=2012-11-23 |title=Structural Analyses of Human Toll-like Receptor 4 Polymorphisms D299G and T399I |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504774/ |journal=The Journal of Biological Chemistry |volume=287 |issue=48 |pages=40611–40617 |doi=10.1074/jbc.M112.404608 |issn=0021-9258 |pmc=3504774 |pmid=23055527}}</ref>.
-== Interactions ==
-TLR4 has been shown to [[Protein-protein interaction|interact]] with:
-* [[Lymphocyte antigen 96]],<ref name="pmid11976338">{{cite journal | vauthors = Re F, Strominger JL | title = Monomeric recombinant MD-2 binds toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness | journal = The Journal of Biological Chemistry | volume = 277 | issue = 26 | pages = 23427–23432 | date = June 2002 | pmid = 11976338 | doi = 10.1074/jbc.M202554200 | s2cid = 18706628 | doi-access = free }}</ref><ref name="pmid10359581">{{cite journal | vauthors = Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, Kimoto M | title = MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4 | journal = The Journal of Experimental Medicine | volume = 189 | issue = 11 | pages = 1777–1782 | date = June 1999 | pmid = 10359581 | pmc = 2193086 | doi = 10.1084/jem.189.11.1777 }}</ref>
-* [[Myd88]],<ref name="pmid15107846">{{cite journal | vauthors = Chuang TH, Ulevitch RJ | title = Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors | journal = Nature Immunology | volume = 5 | issue = 5 | pages = 495–502 | date = May 2004 | pmid = 15107846 | doi = 10.1038/ni1066 | s2cid = 39773935 }}</ref><ref name="pmid12646618">{{cite journal | vauthors = Doyle SE, O'Connell R, Vaidya SA, Chow EK, Yee K, Cheng G | title = Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4 | journal = Journal of Immunology | volume = 170 | issue = 7 | pages = 3565–3571 | date = April 2003 | pmid = 12646618 | doi = 10.4049/jimmunol.170.7.3565 | s2cid = 5239330 | doi-access = free }}</ref><ref name="pmid10952994">{{cite journal | vauthors = Rhee SH, Hwang D | title = Murine TOLL-like receptor 4 confers lipopolysaccharide responsiveness as determined by activation of NF kappa B and expression of the inducible cyclooxygenase | journal = The Journal of Biological Chemistry | volume = 275 | issue = 44 | pages = 34035–34040 | date = November 2000 | pmid = 10952994 | doi = 10.1074/jbc.M007386200 | s2cid = 24729575 | doi-access = free }}</ref><ref name="pmid11544529">{{cite journal | vauthors = Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, Brady G, Brint E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O'Neill LA | display-authors = 6 | title = Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction | journal = Nature | volume = 413 | issue = 6851 | pages = 78–83 | date = September 2001 | pmid = 11544529 | doi = 10.1038/35092578 | s2cid = 4333764 | bibcode = 2001Natur.413...78F }}</ref> and
-* [[TOLLIP]].<ref name="pmid11751856">{{cite journal | vauthors = Zhang G, Ghosh S | title = Negative regulation of toll-like receptor-mediated signaling by Tollip | journal = The Journal of Biological Chemistry | volume = 277 | issue = 9 | pages = 7059–7065 | date = March 2002 | pmid = 11751856 | doi = 10.1074/jbc.M109537200 | s2cid = 30854510 | doi-access = free }}</ref>
-* [[Nickel]],<ref>{{cite journal | vauthors = Peana M, Zdyb K, Medici S, Pelucelli A, Simula G, Gumienna-Kontecka E, Zoroddu MA | title = Ni(II) interaction with a peptide model of the human TLR4 ectodomain | journal = Journal of Trace Elements in Medicine and Biology | volume = 44 | pages = 151–160 | date = December 2017 | pmid = 28965571 | doi = 10.1016/j.jtemb.2017.07.006 }}</ref>
+== Clinical significance==
-Intracellular trafficking of TLR4 is dependent on the GTPase [[RAB11A|Rab-11a]], and knock down of Rab-11a results in hampered TLR4 recruitment to ''E. coli''-containing phagosomes and subsequent reduced signal transduction through the MyD88-independent pathway.<ref name="pmid20933442">{{cite journal | vauthors = Husebye H, Aune MH, Stenvik J, Samstad E, Skjeldal F, Halaas O, Nilsen NJ, Stenmark H, Latz E, Lien E, Mollnes TE, Bakke O, Espevik T | display-authors = 6 | title = The Rab11a GTPase controls Toll-like receptor 4-induced activation of interferon regulatory factor-3 on phagosomes | journal = Immunity | volume = 33 | issue = 4 | pages = 583–596 | date = October 2010 | pmid = 20933442 | doi = 10.1016/j.immuni.2010.09.010 | pmc = 10733841 | doi-access = free }}</ref>
+TLR4 has been reported to play both friend and foe in a variety of human diseases, such as bacterial infections and cancers. This dual role of TLR4 depends on the tyintensity, duration and site (surface or endosome) of its activation, its polymorphism and the balance of activation of signaling pathways (MyD88 ''vs''. TRIF).
-== Clinical significance==
+=== Infectious diseases ===
-Various single nucleotide polymorphisms (SNPs) of the TLR4 in humans have been identified<ref name="pmid = 15766650">{{cite journal | vauthors = Schröder NW, Schumann RR | title = Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease | journal = The Lancet. Infectious Diseases | volume = 5 | issue = 3 | pages = 156–164 | date = March 2005 | pmid = 15766650 | doi = 10.1016/S1473-3099(05)01308-3 }}</ref> and for some of them an association with increased susceptibility to Gram-negative bacterial infections  <ref name="pmid = 11996613">{{cite journal | vauthors = Lorenz E, Mira JP, Frees KL, Schwartz DA | title = Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock | journal = Archives of Internal Medicine | volume = 162 | issue = 9 | pages = 1028–1032 | date = May 2002 | pmid = 11996613 | doi = 10.1001/archinte.162.9.1028 | doi-access = free }}</ref> or faster progression and a more severe course of sepsis in critically ill patients was reported.<ref name="pmid = 24366499">{{cite journal | vauthors = Nachtigall I, Tamarkin A, Tafelski S, Weimann A, Rothbart A, Heim S, Wernecke KD, Spies C | display-authors = 6 | title = Polymorphisms of the toll-like receptor 2 and 4 genes are associated with faster progression and a more severe course of sepsis in critically ill patients | journal = The Journal of International Medical Research | volume = 42 | issue = 1 | pages = 93–110 | date = February 2014 | pmid = 24366499 | doi = 10.1177/0300060513504358 | s2cid = 25824309 | doi-access = free }}</ref>
+TLR4 play a central role in the control of bacterial infections through the recognition of LPS molecules from gram-negative, and some gram-positive, bacteria <ref>{{Cite journal |last=Akira |first=Shizuo |last2=Takeda |first2=Kiyoshi |date=2004-07 |title=Toll-like receptor signalling |url=https://pubmed.ncbi.nlm.nih.gov/15229469/ |journal=Nature Reviews. Immunology |volume=4 |issue=7 |pages=499–511 |doi=10.1038/nri1391 |issn=1474-1733 |pmid=15229469}}</ref>. During infections, TLR4s on innate immunity cells are activated by LPS molecules present in tissues and the bloodstream. This activates innate immunity, the first line of defense against invading microorganisms, and triggers pro-inflammatory responses that facilitate the eradication of invading bacteria <ref>{{Cite journal |last=Molteni |first=Monica |last2=Gemma |first2=Sabrina |last3=Rossetti |first3=Carlo |date=2016 |title=The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887650/ |journal=Mediators of Inflammation |language=en |volume=2016 |doi=10.1155/2016/6978936 |pmid=27293318}}</ref>. Generally, inflammation has a protective role. It is a complex and coordinated process followed by the induction of resolution pathways that restore tissue integrity and function. However, in some cases, exaggerated and uncontrolled [[inflammation]] triggered by TLR4 during [[infection]] can lead to [[sepsis]] and [[septic shock]] <ref name="pmid33057840">{{cite journal |vauthors=Ciesielska A, Matyjek M, Kwiatkowska K |date=February 2021 |title=TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling |journal=Cellular and Molecular Life Sciences |volume=78 |issue=4 |pages=1233–1261 |doi=10.1007/s00018-020-03656-y |pmc=7904555 |pmid=33057840}}</ref>. Infections with Gram-negative bacteria such as [[Escherichia coli|''Escherichia coli'']] and [[Pseudomonas aeruginosa|''Pseudomonas aeruginosa'']] are the prevailing causes of severe sepsis in humans.Some studies have linked TLR4 polymorphisms (Asp299Gly and Thr399Ile SNPs) to an increased susceptibility to sepsis due to gram-negative infection but other studies failed to confirm this <ref>{{Cite journal |last=Netea |first=Mihai G. |last2=Wijmenga |first2=Cisca |last3=O'Neill |first3=Luke A. J. |date=2012-05-18 |title=Genetic variation in Toll-like receptors and disease susceptibility |url=https://pubmed.ncbi.nlm.nih.gov/22610250/ |journal=Nature Immunology |volume=13 |issue=6 |pages=535–542 |doi=10.1038/ni.2284 |issn=1529-2916 |pmid=22610250}}</ref>.
-=== In sepsis ===
+=== In cancer ===
-TLR4 can be activated by binding to the [[lipid A]] portion of [[lipopolysaccharide]] found in [[Gram-negative bacteria]].<ref name="pmid12007641">{{cite journal | vauthors = Lerouge I, Vanderleyden J | title = O-antigen structural variation: mechanisms and possible roles in animal/plant-microbe interactions | journal = FEMS Microbiology Reviews | volume = 26 | issue = 1 | pages = 17–47 | date = March 2002 | pmid = 12007641 | doi = 10.1111/j.1574-6976.2002.tb00597.x | doi-access = free }}</ref>  Exaggerated and uncontrolled [[inflammation]] triggered by TLR4 during [[infection]] can lead to [[sepsis]] and [[septic shock]].<ref name="pmid33057840">{{cite journal | vauthors = Ciesielska A, Matyjek M, Kwiatkowska K | title = TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling | journal = Cellular and Molecular Life Sciences | volume = 78 | issue = 4 | pages = 1233–1261 | date = February 2021 | pmid = 33057840 | pmc = 7904555 | doi = 10.1007/s00018-020-03656-y }}</ref> Infections with Gram-negative bacteria such as ''[[Escherichia coli]]'' and ''[[Pseudomonas aeruginosa]]'' are the prevailing causes of severe sepsis in humans.<ref name="pmid33057840" />
+The role of the TLR4 in the control of cancer progression and in cancer therapy is well documented.
-=== In insulin resistance ===
+Stimulation of TLR4 by natural derivatives and LPS is well known to induce potent antitumor activity. This anti-tumor activity is linked to the ability of LPS to stimulate innate immunity via TLR4, resulting in the production of pro-inflammatory cytokines and type 1 interferons, and the indirect generation of adaptive anti-tumor responses <ref>{{Cite journal |last=Chettab |first=Kamel |last2=Fitzsimmons |first2=Chantel |last3=Novikov |first3=Alexey |last4=Denis |first4=Morgane |last5=Phelip |first5=Capucine |last6=Mathé |first6=Doriane |last7=Choffour |first7=Pierre Antoine |last8=Beaumel |first8=Sabine |last9=Fourmaux |first9=Eric |last10=Norca |first10=Patrick |last11=Kryza |first11=David |last12=Evesque |first12=Anne |last13=Jordheim |first13=Lars Petter |last14=Perrial |first14=Emeline |last15=Matera |first15=Eva-Laure |date=2023 |title=A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models |url=https://pubmed.ncbi.nlm.nih.gov/37223101/ |journal=Frontiers in Immunology |volume=14 |pages=1066402 |doi=10.3389/fimmu.2023.1066402 |issn=1664-3224 |pmid=37223101}}</ref><ref>{{Cite journal |last=Richert |first=Iseulys |last2=Berchard |first2=Paul |last3=Abbes |first3=Lhorra |last4=Novikov |first4=Alexey |last5=Chettab |first5=Kamel |last6=Vandermoeten |first6=Alexandra |last7=Dumontet |first7=Charles |last8=Karanian |first8=Marie |last9=Kerzerho |first9=Jerome |last10=Caroff |first10=Martine |last11=Blay |first11=Jean-Yves |last12=Dutour |first12=Aurélie |date=2023-09-19 |title=A TLR4 Agonist Induces Osteosarcoma Regression by Inducing an Antitumor Immune Response and Reprogramming M2 Macrophages to M1 Macrophages |url=https://pubmed.ncbi.nlm.nih.gov/37760603/ |journal=Cancers |volume=15 |issue=18 |pages=4635 |doi=10.3390/cancers15184635 |issn=2072-6694 |pmid=37760603}}</ref>.
-[[Fetuin|Fetuin-A]] facilitates the binding of lipids to receptors, thereby contributing to [[insulin resistance]].<ref>{{cite journal | vauthors = Icer MA, Yıldıran H | title = Effects of fetuin-A with diverse functions and multiple mechanisms on human health | journal = Clinical Biochemistry | volume = 88 | pages = 1–10 | date = February 2021 | pmid = 33245873 | doi = 10.1016/j.clinbiochem.2020.11.004 | s2cid = 227190375 }}</ref>
+The first clues about the efficacy of TLR4 agonists like LPS in cancer immunotherapy was found in the 19th centuries, when bacterial infections were found to induce tumor regressions <ref>{{Cite journal |last=Maruyama |first=Kouji |last2=Selmani |first2=Zohair |last3=Ishii |first3=Hidee |last4=Yamaguchi |first4=Ken |date=2011-03 |title=Innate immunity and cancer therapy |url=https://pubmed.ncbi.nlm.nih.gov/20955832/ |journal=International Immunopharmacology |volume=11 |issue=3 |pages=350–357 |doi=10.1016/j.intimp.2010.09.012 |issn=1878-1705 |pmid=20955832}}</ref>. Later, Dr William Coley showed the therapeutic efficacy of a mixed bacterial vaccine, so-called “Coley’s toxin”, to human cancer <ref>{{Cite journal |last=Starnes |first=C. O. |date=1992-05-07 |title=Coley's toxins in perspective |url=https://pubmed.ncbi.nlm.nih.gov/1574121/ |journal=Nature |volume=357 |issue=6373 |pages=11–12 |doi=10.1038/357011a0 |issn=0028-0836 |pmid=1574121}}</ref>. Since then, a number of developments have been made in the treatment or prevention of cancer using bacterial mixtures strongly activating TLR4 due to LPS content. The antituberculosis vaccine [[Bacillus Calmette–Guérin]] (BCG) was approved by the Federal Drug Administration (FDA) in 1990 for the local treatment of superficial bladder cancer. BCG promotes dendritic cell maturation, and this effect is TLR4 (as well as TLR2) dependent <ref>{{Cite journal |last=Tsuji |first=Shoutaro |last2=Matsumoto |first2=Misako |last3=Takeuchi |first3=Osamu |last4=Akira |first4=Shizuo |last5=Azuma |first5=Ichiro |last6=Hayashi |first6=Akira |last7=Toyoshima |first7=Kumao |last8=Seya |first8=Tsukasa |date=2000-12 |editor-last=Kaufmann |editor-first=S. H. E. |title=Maturation of Human Dendritic Cells by Cell Wall Skeleton of Mycobacterium bovis Bacillus Calmette-Guérin: Involvement of Toll-Like Receptors |url=https://journals.asm.org/doi/10.1128/IAI.68.12.6883-6890.2000 |journal=Infection and Immunity |language=en |volume=68 |issue=12 |pages=6883–6890 |doi=10.1128/IAI.68.12.6883-6890.2000 |issn=0019-9567 |pmc=PMC97794 |pmid=11083809}}</ref>. There are also reports on the treatment of oral [[squamous cell carcinoma]], gastric , Head-and-neck and [[cervical cancer]]<nowiki/>s with lyophilized streptococcal preparation OK-432 (Picibanil) <ref>{{Cite journal |last=Ryoma |first=Yoshiki |last2=Moriya |first2=Yoichiro |last3=Okamoto |first3=Masato |last4=Kanaya |first4=Isao |last5=Saito |first5=Motoo |last6=Sato |first6=Mitsunobu |date=2004-09-01 |title=Biological Effect of OK-432 (Picibanil) and Possible Application to Dendritic Cell Therapy |url=https://ar.iiarjournals.org/content/24/5C/3295 |journal=Anticancer Research |language=en |volume=24 |issue=5C |pages=3295–3302 |issn=0250-7005 |pmid=15515424}}</ref>. The mechanism of action of OK-432 involves TLR4 activation, since OKA-432 does not inhibit tumor growth on TLR4 knockouts as it does on wild-type mice <ref>{{Cite web |url=https://academic.oup.com/jnci/article/95/4/316/2520610 |access-date=2024-02-20 |website=academic.oup.com}}</ref>.
-=== In cancer progression ===
+Purified LPS also showed potent anti-tumor efficacy as systemic therapeutic agents in several tumor models <ref>{{Cite web |url=https://academic.oup.com/jnci/article-abstract/4/5/461/905560 |access-date=2024-02-20 |website=academic.oup.com}}</ref><ref>{{Cite journal |last=Berendt |first=M. J. |last2=North |first2=R. J. |last3=Kirstein |first3=D. P. |date=1978-12-01 |title=The immunological basis of endotoxin-induced tumor regression. Requirement for a pre-existing state of concomitant anti-tumor immunity |url=https://pubmed.ncbi.nlm.nih.gov/309922/ |journal=The Journal of Experimental Medicine |volume=148 |issue=6 |pages=1560–1569 |doi=10.1084/jem.148.6.1560 |issn=0022-1007 |pmc=2185097 |pmid=309922}}</ref>. In the 90’s, clinical trials evaluating the intravenous administration of LPS to patients with cancer provided positive results including several cases of disease stabilization and partial responses. However, limiting toxicities at doses in the ng/kg range has been reported which are too low to obtain significant antitumor effects <ref>{{Cite journal |last=Engelhardt |first=R. |last2=Mackensen |first2=A. |last3=Galanos |first3=C. |date=1991-05-15 |title=Phase I trial of intravenously administered endotoxin (Salmonella abortus equi) in cancer patients |url=https://pubmed.ncbi.nlm.nih.gov/2021932/ |journal=Cancer Research |volume=51 |issue=10 |pages=2524–2530 |issn=0008-5472 |pmid=2021932}}</ref>.
-TLR4 expression can be detected on many tumor cells and cell lines. TLR4 is capable of activating [[MAPK]] and [[NF-κB]] pathways, implicating possible direct role of cell-autonomous TLR4 signaling in regulation of carcinogenesis, in particular, through increased proliferation of tumor cells, [[apoptosis]] inhibition and [[metastasis]]. TLR4 signaling may also contribute to resistance to [[paclitaxel]] chemotherapy in [[ovary cancer]] and [[siRNA]] therapy in [[prostate cancer]]. 63% of [[breast cancer]] patients were reported to express TLR4 on tumor cells and the level of expression inversely correlated with the survival. Additionally, low [[MyD88]] expression correlated with decreased metastasis to the lung and decreased [[CCL2]] and [[CCL5]] expression. TLR4 expression levels were the highest among TLRs in human breast cancer cell line [[MDA-MB-231]] and TLR4 knockdown resulted in decreased proliferation and decreased [[Interleukin 6|IL-6]] and [[Interleukin 8|IL-8]] levels. On the other hand, TLR4 signaling in immune and inflammatory cells of [[tumor microenvironment]] may lead to production of proinflammatory cytokines ([[Tumor necrosis factor superfamily|TNF]], [[IL-1β]], IL-6, [[Interleukin 18|IL-18]], etc.), immunosuppressive cytokines ([[Interleukin 10|IL-10]], [[TGF-β]], etc.) and angiogenic mediators ([[VEGF]], [[Epidermal growth factor|EGF]], TGF-β, etc.).
+Subsequently, detoxified TLR4 agonists (LPS derivatives) have been produced and evaluated in the clinic. This includes the MPL, a chemically modified LPS which was the first TLR4 agonist to be approved and commercialized by GSK in 5 human vaccines (HPV, Zoster, Hepatitis B, Malaria, RSV). MPL was investigated as an adjuvant for curative anti-tumor vaccines, with the approval of Melacine in Canada for the treatment of patients with malignant melanoma <ref>{{Cite web |title=Melacine - an overview {{!}} ScienceDirect Topics |url=https://www.sciencedirect.com/topics/medicine-and-dentistry/melacine |access-date=2024-02-20 |website=www.sciencedirect.com}}</ref>. Synthetic LPS derivatives based on dephosphorylated lipid A moiety structures were also developed and confirmed potent adjuvant and antitumor activities as therapeutic agents. In particular, the intratumoral administration of Glucopyranosyl Lipid Adjuvant (GLA-SE/G100), a synthetic detoxified analog of lipid A formulated in a stable emulsion, showed anti-tumor immune responses and tumor regression in patients with Merkel cell carcinoma <ref>{{Cite journal |last=Bhatia |first=Shailender |last2=Miller |first2=Natalie J. |last3=Lu |first3=Hailing |last4=Longino |first4=Natalie V. |last5=Ibrani |first5=Dafina |last6=Shinohara |first6=Michi M. |last7=Byrd |first7=David R. |last8=Parvathaneni |first8=Upendra |last9=Kulikauskas |first9=Rima |last10=Ter Meulen |first10=Jan |last11=Hsu |first11=Frank J. |last12=Koelle |first12=David M. |last13=Nghiem |first13=Paul |date=2019-02-15 |title=Intratumoral G100, a TLR4 Agonist, Induces Antitumor Immune Responses and Tumor Regression in Patients with Merkel Cell Carcinoma |url=https://pubmed.ncbi.nlm.nih.gov/30093453/ |journal=Clinical Cancer Research: An Official Journal of the American Association for Cancer Research |volume=25 |issue=4 |pages=1185–1195 |doi=10.1158/1078-0432.CCR-18-0469 |issn=1557-3265 |pmc=6368904 |pmid=30093453}}</ref>, and potent adjuvant activity in phase 2 trials in combination with pembrolizumab in patients with follicular lymphoma <ref>{{Cite journal |last=Halwani |first=Ahmad S. |last2=Panizo |first2=Carlos |last3=Isufi |first3=Iris |last4=Herrera |first4=Alex F. |last5=Okada |first5=Craig Y. |last6=Cull |first6=Elizabeth H. |last7=Kis |first7=Bela |last8=Chaves |first8=Jorge M. |last9=Bartlett |first9=Nancy L. |last10=Ai |first10=Weiyun |last11=de la Cruz-Merino |first11=Luis |last12=Bryan |first12=Locke J. |last13=Houot |first13=Roch |last14=Linton |first14=Kim |last15=Briones |first15=Javier |date=2022-04 |title=Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma |url=https://pubmed.ncbi.nlm.nih.gov/34865586/ |journal=Leukemia & Lymphoma |volume=63 |issue=4 |pages=821–833 |doi=10.1080/10428194.2021.2010057 |issn=1029-2403 |pmid=34865586}}</ref><ref>{{Cite journal |last=Flowers |first=Christopher |last2=Panizo |first2=Carlos |last3=Isufi |first3=Iris |last4=Herrera |first4=Alex F. |last5=Okada |first5=Craig |last6=Cull |first6=Elizabeth H. |last7=Kis |first7=Bela |last8=Chaves |first8=Jorge M. |last9=Bartlett |first9=Nancy L. |last10=Ai |first10=Weiyun |last11=de la Cruz-Merino |first11=Luis |last12=Bryan |first12=Locke J. |last13=Houot |first13=Roch |last14=Linton |first14=Kim |last15=Briones |first15=Javier |date=2017-12-08 |title=Intratumoral G100 Induces Systemic Immunity and Abscopal Tumor Regression in Patients with Follicular Lymphoma: Results of a Phase 1/ 2 Study Examining G100 Alone and in Combination with Pembrolizumab |url=https://www.sciencedirect.com/science/article/pii/S0006497119832871 |journal=Blood |volume=130 |pages=2771 |doi=10.1182/blood.V130.Suppl_1.2771.2771 |issn=0006-4971}}</ref>.
-These activities may result in further polarization of [[tumor-associated macrophage]]s, conversion of [[fibroblasts]] into tumor-promoting cancer-associated fibroblasts, conversion of dendritic cells into tumor-associated DCs and activation of pro-tumorigenic functions of immature myeloid cells - [[Myeloid-derived Suppressor Cell]]s (MDSC). TLR signaling has been linked to accumulation and function of MDSC at the site of tumor and it also allows mesenchymal stromal cells to counter [[NK cell]]-mediated anti-tumor immunity. In HepG2 hepatoblastoma cells LPS increased TLR4 levels, [[cell proliferation]] and resistance to [[chemotherapy]], and these phenomena could be reversed by TLR4 [[gene knockdown]]. Similarly, LPS stimulation of human liver cancer cell line H7402 resulted in TLR4 upregulation, NF-κB activation, TNF, IL-6 and IL-8 production and increased proliferation that could be reversed by signal transducer
-and [[STAT3]] inhibition. Besides the successful usage of [[Bacillus Calmette–Guérin]] in the therapy of [[bladder cancer]] there are reports on the treatment of oral [[squamous cell carcinoma]], [[gastric cancer]] and [[cervical cancer]] with lyophilized streptococcal preparation OK-432 and utilization of TLR4/[[TLR2]] ligands – derivatives of [[muramyl dipeptide]].<ref name="sciencedirect.com"/>
+Besides the recognized anti-tumor efficacy of TLR4 activation by LPS, some studies suggest that TLR4 may also contribute to the development of some cancers, (prostate, liver, breast and lung cancers) and may contribute to resistance to [[paclitaxel]] chemotherapy in breast cancer <ref>{{Cite journal |last=Rajput |first=Sandeep |last2=Volk-Draper |first2=Lisa D. |last3=Ran |first3=Sophia |date=2013-08 |title=TLR4 is a novel determinant of the response to paclitaxel in breast cancer |url=https://pubmed.ncbi.nlm.nih.gov/23720768/ |journal=Molecular Cancer Therapeutics |volume=12 |issue=8 |pages=1676–1687 |doi=10.1158/1535-7163.MCT-12-1019 |issn=1538-8514 |pmc=3742631 |pmid=23720768}}</ref>. Some clinical studies also suggested a potential correlation between TLR4 expression on tumor cells and tumor progression. However, no such effect was reported in the numerous clinical studies conducted with natural LPS or LPS derivatives. On the contrary, in phase 2 studies with GLA, a positive association between baseline TLR4 expression in tumors and the increase of overall response rates has been reported <ref>{{Cite journal |last=Flowers |first=Christopher |last2=Panizo |first2=Carlos |last3=Isufi |first3=Iris |last4=Herrera |first4=Alex F. |last5=Okada |first5=Craig |last6=Cull |first6=Elizabeth H. |last7=Kis |first7=Bela |last8=Chaves |first8=Jorge M. |last9=Bartlett |first9=Nancy L. |last10=Ai |first10=Weiyun |last11=de la Cruz-Merino |first11=Luis |last12=Bryan |first12=Locke J. |last13=Houot |first13=Roch |last14=Linton |first14=Kim |last15=Briones |first15=Javier |date=2017-12-08 |title=Intratumoral G100 Induces Systemic Immunity and Abscopal Tumor Regression in Patients with Follicular Lymphoma: Results of a Phase 1/ 2 Study Examining G100 Alone and in Combination with Pembrolizumab |url=https://www.sciencedirect.com/science/article/pii/S0006497119832871 |journal=Blood |volume=130 |pages=2771 |doi=10.1182/blood.V130.Suppl_1.2771.2771 |issn=0006-4971}}</ref>.
-TLR4 stimulates B-cell responsiveness to [[Pokeweed mitogen]] for proliferation which can play a role in inhibiting tumor development.<ref>{{cite journal | vauthors = Bekeredjian-Ding I, Foermer S, Kirschning CJ, Parcina M, Heeg K | title = Poke weed mitogen requires Toll-like receptor ligands for proliferative activity in human and murine B lymphocytes | journal = PLOS ONE | volume = 7 | issue = 1 | pages = e29806 | date = 2012-01-04 | pmid = 22238657 | pmc = 3251602 | doi = 10.1371/journal.pone.0029806 | doi-access = free | bibcode = 2012PLoSO...729806B }}</ref>
+The potential impact of TLR4 on the progression of some cancers was associated with the excessive production of pro-inflammatory cytokines via activation of the TLR4-MyD88/NF-kB signaling pathway <ref>{{Cite journal |last=Zhang |first=Rui |last2=Zhao |first2=Jian |last3=Xu |first3=Jian |last4=Jiao |first4=De-Xin |last5=Wang |first5=Jian |last6=Gong |first6=Zhi-Qiang |last7=Jia |first7=Jian-Hui |date=2017-10 |title=Andrographolide suppresses proliferation of human colon cancer SW620 cells through the TLR4/NF-κB/MMP-9 signaling pathway |url=https://pubmed.ncbi.nlm.nih.gov/28943944/ |journal=Oncology Letters |volume=14 |issue=4 |pages=4305–4310 |doi=10.3892/ol.2017.6669 |issn=1792-1074 |pmc=5604146 |pmid=28943944}}</ref><ref>{{Cite journal |last=Wang |first=C.-H. |last2=Wang |first2=P.-J. |last3=Hsieh |first3=Y.-C. |last4=Lo |first4=S. |last5=Lee |first5=Y.-C. |last6=Chen |first6=Y.-C. |last7=Tsai |first7=C.-H. |last8=Chiu |first8=W.-C. |last9=Chu-Sung Hu |first9=S. |last10=Lu |first10=C.-W. |last11=Yang |first11=Y.-F. |last12=Chiu |first12=C.-C. |last13=Ou-Yang |first13=F. |last14=Wang |first14=Y.-M. |last15=Hou |first15=M.-F. |date=2018-02-01 |title=Resistin facilitates breast cancer progression via TLR4-mediated induction of mesenchymal phenotypes and stemness properties |url=https://pubmed.ncbi.nlm.nih.gov/28991224/ |journal=Oncogene |volume=37 |issue=5 |pages=589–600 |doi=10.1038/onc.2017.357 |issn=1476-5594 |pmid=28991224}}</ref><ref>{{Cite journal |last=Kelly |first=Michael G. |last2=Alvero |first2=Ayesha B. |last3=Chen |first3=Rui |last4=Silasi |first4=Dan-Arin |last5=Abrahams |first5=Vikki M. |last6=Chan |first6=Serena |last7=Visintin |first7=Irene |last8=Rutherford |first8=Thomas |last9=Mor |first9=Gil |date=2006-04-01 |title=TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer |url=https://pubmed.ncbi.nlm.nih.gov/16585214/ |journal=Cancer Research |volume=66 |issue=7 |pages=3859–3868 |doi=10.1158/0008-5472.CAN-05-3948 |issn=0008-5472 |pmid=16585214}}</ref>. Several studies showed that this is mediated by the misuse of DAMP signaling by tumor cells <ref>{{Cite journal |last=Jang |first=Gun-Young |last2=Lee |first2=Ji Won |last3=Kim |first3=Young Seob |last4=Lee |first4=Sung Eun |last5=Han |first5=Hee Dong |last6=Hong |first6=Kee-Jong |last7=Kang |first7=Tae Heung |last8=Park |first8=Yeong-Min |date=2020-12 |title=Interactions between tumor-derived proteins and Toll-like receptors |url=https://pubmed.ncbi.nlm.nih.gov/33299138/ |journal=Experimental & Molecular Medicine |volume=52 |issue=12 |pages=1926–1935 |doi=10.1038/s12276-020-00540-4 |issn=2092-6413 |pmc=8080774 |pmid=33299138}}</ref><ref>{{Cite journal |last=Khademalhosseini |first=Morteza |last2=Arababadi |first2=Mohammad Kazemi |date=2019-05-01 |title=Toll-like receptor 4 and breast cancer: an updated systematic review |url=https://doi.org/10.1007/s12282-018-00935-2 |journal=Breast Cancer |language=en |volume=26 |issue=3 |pages=265–271 |doi=10.1007/s12282-018-00935-2 |issn=1880-4233}}</ref><ref>{{Cite journal |last=Roh |first=Jong Seong |last2=Sohn |first2=Dong Hyun |date=2018-08 |title=Damage-Associated Molecular Patterns in Inflammatory Diseases |url=https://pubmed.ncbi.nlm.nih.gov/30181915/ |journal=Immune Network |volume=18 |issue=4 |pages=e27 |doi=10.4110/in.2018.18.e27 |issn=1598-2629 |pmc=6117512 |pmid=30181915}}</ref>.
-=== In pregnancy ===
-Activation of TLR4 in intrauterine infections leads to deregulation of prostaglandin synthesis, leading to uterine smooth muscle contraction.{{Citation needed|date=November 2021}}
+Many DAMPs are released by dying or necrotic tumor cells and present during cancer progression. DAMPs released from tumor cells can directly activate tumor-expressed TLR4 that induce chemoresistance, migration, invasion, and metastasis. Furthermore, DAMP-induced chronic inflammation in the tumor microenvironment causes an increase in immunosuppressive populations, such as M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) <ref>{{Cite journal |last=Jang |first=Gun-Young |last2=Lee |first2=Ji Won |last3=Kim |first3=Young Seob |last4=Lee |first4=Sung Eun |last5=Han |first5=Hee Dong |last6=Hong |first6=Kee-Jong |last7=Kang |first7=Tae Heung |last8=Park |first8=Yeong-Min |date=2020-12 |title=Interactions between tumor-derived proteins and Toll-like receptors |url=https://pubmed.ncbi.nlm.nih.gov/33299138/ |journal=Experimental & Molecular Medicine |volume=52 |issue=12 |pages=1926–1935 |doi=10.1038/s12276-020-00540-4 |issn=2092-6413 |pmc=8080774 |pmid=33299138}}</ref>. DAMPs, such as HMGB1, S100 proteins, and heat shock proteins (HSPs), were found to strongly activate inflammatory pathways and release IL-1, IL-6, LT-β, IFN-γ, TNF, and transforming growth factor (TGF)-β promoting inflammation, immunosuppression, angiogenesis, and tumor cell proliferation <ref>{{Cite journal |last=Hernandez |first=C. |last2=Huebener |first2=P. |last3=Schwabe |first3=R. F. |date=2016-11-17 |title=Damage-associated molecular patterns in cancer: a double-edged sword |url=https://pubmed.ncbi.nlm.nih.gov/27086930/ |journal=Oncogene |volume=35 |issue=46 |pages=5931–5941 |doi=10.1038/onc.2016.104 |issn=1476-5594 |pmc=5119456 |pmid=27086930}}</ref>.
-=== Asp299Gly polymorphism ===
+Several studies have evaluated the potential association of this TLR4 polymorphism with cancer risk, but the data are highly conflicting. However, some meta-analyses suggest an association of SNP D299G with gastric, viral-induced and female-specific cancers (cervix, ovary) <ref>{{Cite journal |last=Zhu |first=Longbiao |last2=Yuan |first2=Hua |last3=Jiang |first3=Tao |last4=Wang |first4=Ruixia |last5=Ma |first5=Hongxia |last6=Zhang |first6=Shuangyue |date=2013-12-20 |title=Association of TLR2 and TLR4 Polymorphisms with Risk of Cancer: A Meta-Analysis |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869723/ |journal=PLoS ONE |volume=8 |issue=12 |pages=e82858 |doi=10.1371/journal.pone.0082858 |issn=1932-6203 |pmc=3869723 |pmid=24376595}}</ref>.
-Classically, TLR4 is said to be the receptor for [[Lipopolysaccharide|LPS]], however TLR4 has also been shown to be activated by other kinds of lipids. ''[[Plasmodium falciparum]]'', a parasite known to cause the most common and serious form of [[malaria]] that is seen primarily in Africa, produces [[glycosylphosphatidylinositol]], which can activate TLR4.<ref name="Theory1">{{cite journal | vauthors = Mockenhaupt FP, Cramer JP, Hamann L, Stegemann MS, Eckert J, Oh NR, Otchwemah RN, Dietz E, Ehrhardt S, Schröder NW, Bienzle U, Schumann RR | display-authors = 6 | title = Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 1 | pages = 177–182 | date = January 2006 | pmid = 16371473 | pmc = 1324982 | doi = 10.1073/pnas.0506803102 | ref = Mal1 | doi-access = free | bibcode = 2006PNAS..103..177M }}</ref> Two [[Single Nucleotide Polymorphisms|SNPs]] in TLR4 are co-expressed with high [[penetrance]] in African populations (i.e. TLR-4-Asp299Gly and TLR-4-Thr399Ile). These Polymorphisms are associated with an increase in TLR4-Mediated [[Interleukin 10|IL-10]] production—an immunomodulator—and a decrease in [[proinflammatory cytokine]]s.<ref name="Cyt1">{{cite journal | vauthors = Van der Graaf CA, Netea MG, Morré SA, Den Heijer M, Verweij PE, Van der Meer JW, Kullberg BJ | title = Toll-like receptor 4 Asp299Gly/Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection | journal = European Cytokine Network | volume = 17 | issue = 1 | pages = 29–34 | date = March 2006 | pmid = 16613760 | url = http://www.jle.com/fr/revues/ecn/e-docs/toll_like_receptor_4_asp299gly_thr399ile_polymorphisms_are_a_risk_factor_for_candida_bloodstream_infection_268300/article.phtml | ref = Cyt1 }}</ref> The TLR-4-Asp299Gly point mutation is strongly correlated with an increased infection rate with ''Plasmodium falciparum''. It appears that the mutation prevents TLR4 from acting as vigorously against, at least some plasmodial infections. The [[malaria]] infection rate and associated morbidity are higher in TLR-4-Asp299Gly group, but mortality appears to be decreased. This may indicate that at least part of the pathogenesis of [[malaria]] takes advantage of cytokine production. By reducing the cytokine production via the TLR4 mutation, the infection rate may increase, but the number of deaths due to the infection seem to decrease.<ref name="Theory1" />
+=== '''In neurogenerative diseases''' ===
-In addition, TLR4-D299G has been associated with aggressive colorectal cancer in humans. It has been shown that human colon adenocarcinomas from patients with TLR4-D299G were more frequently of an advanced stage with metastasis than those with wild-type TLR4.  The same study demonstrated functionally that intestinal epithelial cells (Caco-2) expressing TLR4-D299G underwent epithelial-mesenchymal transition and morphologic changes associated with tumor progression, whereas intestinal epithelial cells expressing wild-type TLR4 did not.<ref>{{cite journal | vauthors = Eyking A, Ey B, Rünzi M, Roig AI, Reis H, Schmid KW, Gerken G, Podolsky DK, Cario E | display-authors = 6 | title = Toll-like receptor 4 variant D299G induces features of neoplastic progression in Caco-2 intestinal cells and is associated with advanced human colon cancer | journal = Gastroenterology | volume = 141 | issue = 6 | pages = 2154–2165 | date = December 2011 | pmid = 21920464 | pmc = 3268964 | doi = 10.1053/j.gastro.2011.08.043 }}</ref>
+Growing evidence suggests an implication of TLR4 in the development and progression of neurogenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. In the brain, TLR4 is expressed by neurons as well as the non-neuronal glial cells, which include microglia, astrocytes, and oligodendrocytes. TLR4 is expressed primarily by microglia, and to a lesser extent by astrocytes, oligodendrocytes, and neurons <ref>{{Cite journal |last=Vaure |first=Céline |last2=Liu |first2=Yuanqing |date=2014 |title=A Comparative Review of Toll-Like Receptor 4 Expression and Functionality in Different Animal Species |url=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00316 |journal=Frontiers in Immunology |volume=5 |doi=10.3389/fimmu.2014.00316/full |issn=1664-3224}}</ref>. Microglia are representatives of the mononuclear phagocyte system in the brain, and TLR4 activation regulates some of their functions, such as phagocytic activity <ref>{{Cite journal |last=Wardill |first=Hannah R. |last2=Van Sebille |first2=Ysabella Z. A. |last3=Mander |first3=Kimberley A. |last4=Gibson |first4=Rachel J. |last5=Logan |first5=Richard M. |last6=Bowen |first6=Joanne M. |last7=Sonis |first7=Stephen T. |date=2015-02 |title=Toll-like receptor 4 signaling: a common biological mechanism of regimen-related toxicities: an emerging hypothesis for neuropathy and gastrointestinal toxicity |url=https://pubmed.ncbi.nlm.nih.gov/25512119/ |journal=Cancer Treatment Reviews |volume=41 |issue=2 |pages=122–128 |doi=10.1016/j.ctrv.2014.11.005 |issn=1532-1967 |pmid=25512119}}</ref><ref>{{Cite journal |last=Molteni |first=Monica |last2=Gemma |first2=Sabrina |last3=Rossetti |first3=Carlo |date=2016 |title=The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation |url=https://pubmed.ncbi.nlm.nih.gov/27293318/ |journal=Mediators of Inflammation |volume=2016 |pages=6978936 |doi=10.1155/2016/6978936 |issn=1466-1861 |pmc=4887650 |pmid=27293318}}</ref>.
+Activation of microglial TLR4 has been suggested to protect against or slow the development of neurodegenerative diseases, notably by enhancing the clearance of neurotoxic proteins such as Aβ and its aggregates, thanks to increased phagocytic and autophagic activity <ref>{{Cite journal |last=Tahara |first=Kazuki |last2=Kim |first2=Hong-Duck |last3=Jin |first3=Jing-Ji |last4=Maxwell |first4=J. Adam |last5=Li |first5=Ling |last6=Fukuchi |first6=Ken-ichiro |date=2006-11 |title=Role of toll-like receptor signalling in Abeta uptake and clearance |url=https://pubmed.ncbi.nlm.nih.gov/16984903/ |journal=Brain: A Journal of Neurology |volume=129 |issue=Pt 11 |pages=3006–3019 |doi=10.1093/brain/awl249 |issn=1460-2156 |pmc=2445613 |pmid=16984903}}</ref>.
-== Animal studies ==
+However, chronic TLR4 activation is believed to be associated with glia-mediated neuronal death due to excessive secretion of pro-inflammatory cytotoxins leading to neuroinflammation, a key factor in the development of many neurodegenerative diseases <ref>{{Cite journal |last=Buchanan |first=Madison M. |last2=Hutchinson |first2=Mark |last3=Watkins |first3=Linda R. |last4=Yin |first4=Hang |date=2010-7 |title=Toll-like Receptor 4 in CNS Pathologies |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909662/ |journal=Journal of neurochemistry |volume=114 |issue=1 |pages=13–27 |doi=10.1111/j.1471-4159.2010.06736.x |issn=0022-3042 |pmc=2909662 |pmid=20402965}}</ref><ref>{{Cite journal |last=Qin |first=Yiren |last2=Liu |first2=Yang |last3=Hao |first3=Wenlin |last4=Decker |first4=Yann |last5=Tomic |first5=Inge |last6=Menger |first6=Michael D. |last7=Liu |first7=Chunfeng |last8=Fassbender |first8=Klaus |date=2016-10-15 |title=Stimulation of TLR4 Attenuates Alzheimer's Disease-Related Symptoms and Pathology in Tau-Transgenic Mice |url=https://pubmed.ncbi.nlm.nih.gov/27605009/ |journal=Journal of Immunology (Baltimore, Md.: 1950) |volume=197 |issue=8 |pages=3281–3292 |doi=10.4049/jimmunol.1600873 |issn=1550-6606 |pmid=27605009}}</ref>. In the brain, TLR4 can be activated by various endogenous DAMPs in addition to pathology-associated proteins such as aggregates of amyloid-βpeptides (Aβ) or α-synuclein <ref>{{Cite journal |last=Gambuzza |first=M. |last2=Licata |first2=N. |last3=Palella |first3=E. |last4=Celi |first4=D. |last5=Foti Cuzzola |first5=V. |last6=Italiano |first6=D. |last7=Marino |first7=S. |last8=Bramanti |first8=P. |date=2011-10-28 |title=Targeting Toll-like receptors: emerging therapeutics for multiple sclerosis management |url=https://pubmed.ncbi.nlm.nih.gov/21889214/ |journal=Journal of Neuroimmunology |volume=239 |issue=1-2 |pages=1–12 |doi=10.1016/j.jneuroim.2011.08.010 |issn=1872-8421 |pmid=21889214}}</ref>. All these structures bind TLR4 and activate downstream signaling pathways in glia, inducing secretion of reactive oxygen species (ROS) and proinflammatory cytokines such as IL-1β and TNF-α, which can lead to damage and death of neurons <ref>{{Cite journal |last=Buchanan |first=Madison M. |last2=Hutchinson |first2=Mark |last3=Watkins |first3=Linda R. |last4=Yin |first4=Hang |date=2010-7 |title=Toll-like Receptor 4 in CNS Pathologies |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909662/ |journal=Journal of neurochemistry |volume=114 |issue=1 |pages=13–27 |doi=10.1111/j.1471-4159.2010.06736.x |issn=0022-3042 |pmc=2909662 |pmid=20402965}}</ref><ref>{{Cite journal |last=Rannikko |first=Emmy H. |last2=Weber |first2=Stephanie S. |last3=Kahle |first3=Philipp J. |date=2015-09-07 |title=Exogenous α-synuclein induces toll-like receptor 4 dependent inflammatory responses in astrocytes |url=https://pubmed.ncbi.nlm.nih.gov/26346361/ |journal=BMC neuroscience |volume=16 |pages=57 |doi=10.1186/s12868-015-0192-0 |issn=1471-2202 |pmc=4562100 |pmid=26346361}}</ref><ref>{{Cite journal |last=Walter |first=Silke |last2=Letiembre |first2=Maryse |last3=Liu |first3=Yang |last4=Heine |first4=Holger |last5=Penke |first5=Botond |last6=Hao |first6=Wenlin |last7=Bode |first7=Barbara |last8=Manietta |first8=Nicole |last9=Walter |first9=Jessica |last10=Schulz-Schuffer |first10=Walter |last11=Fassbender |first11=Klaus |date=2007 |title=Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease |url=https://pubmed.ncbi.nlm.nih.gov/17982277/ |journal=Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology |volume=20 |issue=6 |pages=947–956 |doi=10.1159/000110455 |issn=1015-8987 |pmid=17982277}}</ref>. Neuronal death is accompanied by the release of DAMPs into the extracellular space, which can then further activate TLR4, aggravating neuroinflammation <ref>{{Cite journal |last=Land |first=Walter G. |date=2015-02 |title=The Role of Damage-Associated Molecular Patterns in Human Diseases: Part I - Promoting inflammation and immunity |url=https://pubmed.ncbi.nlm.nih.gov/25685392/ |journal=Sultan Qaboos University Medical Journal |volume=15 |issue=1 |pages=e9–e21 |issn=2075-051X |pmc=4318613 |pmid=25685392}}</ref>. In patients with Alzheimer's disease (AD), the levels of circulating DAMPs like HMGB1 and soluble RAGE, are significantly elevated, which was correlated with the levels of amyloid beta <ref>{{Cite journal |last=Festoff |first=Barry W. |last2=Sajja |first2=Ravi K. |last3=van Dreden |first3=Patrick |last4=Cucullo |first4=Luca |date=2016-08-24 |title=HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer's disease |url=https://pubmed.ncbi.nlm.nih.gov/27553758/ |journal=Journal of Neuroinflammation |volume=13 |issue=1 |pages=194 |doi=10.1186/s12974-016-0670-z |issn=1742-2094 |pmc=4995775 |pmid=27553758}}</ref>. In AD patients, the serum levels of S100B are also intimately related to the severity of the disease <ref>{{Cite journal |last=Chaves |first=Márcia L. |last2=Camozzato |first2=Ana L. |last3=Ferreira |first3=Eduardo D. |last4=Piazenski |first4=Isabel |last5=Kochhann |first5=Renata |last6=Dall'Igna |first6=Oscar |last7=Mazzini |first7=Guilherme S. |last8=Souza |first8=Diogo O. |last9=Portela |first9=Luis V. |date=2010-01-27 |title=Serum levels of S100B and NSE proteins in Alzheimer's disease patients |url=https://pubmed.ncbi.nlm.nih.gov/20105309/ |journal=Journal of Neuroinflammation |volume=7 |pages=6 |doi=10.1186/1742-2094-7-6 |issn=1742-2094 |pmc=2832635 |pmid=20105309}}</ref>. The role of the HMGB1-TLR4 axis is very important in the pathogenesis of Parkinson's disease (PD). The serum HMGB1 and TLR4 protein levels were significantly elevated in PD patients and correlated with the PD stages <ref>{{Cite journal |last=Yang |first=Yi |last2=Han |first2=Chenyang |last3=Guo |first3=Li |last4=Guan |first4=Qiaobin |date=2018-04 |title=High expression of the HMGB1-TLR4 axis and its downstream signaling factors in patients with Parkinson's disease and the relationship of pathological staging |url=https://pubmed.ncbi.nlm.nih.gov/29670828/ |journal=Brain and Behavior |volume=8 |issue=4 |pages=e00948 |doi=10.1002/brb3.948 |issn=2162-3279 |pmc=5893335 |pmid=29670828}}</ref>.
-A link between the TLR4 receptor and [[binge drinking]] has been suggested. When genes responsible for the expression of TLR4 and [[GABA]] receptors are manipulated in rodents that had been bred and trained to drink excessively, the animals showed a "profound reduction" in drinking behaviours.<ref name="pmid21368176">{{cite journal | vauthors = Liu J, Yang AR, Kelly T, Puche A, Esoga C, June HL, Elnabawi A, Merchenthaler I, Sieghart W, June HL, Aurelian L | display-authors = 6 | title = Binge alcohol drinking is associated with GABAA alpha2-regulated Toll-like receptor 4 (TLR4) expression in the central amygdala | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 11 | pages = 4465–4470 | date = March 2011 | pmid = 21368176 | pmc = 3060224 | doi = 10.1073/pnas.1019020108 | doi-access = free | bibcode = 2011PNAS..108.4465L }}
-*{{lay source |template = cite press release |url = https://www.sciencedaily.com/releases/2011/02/110228151911.htm  |title = Genes associated with binge drinking identified|date= March 1, 2011 |website = sciencedaily.com }}</ref> Additionally, it has been shown that ethanol, even in the absence of LPS, can activate TLR4 signaling pathways.<ref name="pmid16272348">{{cite journal | vauthors = Blanco AM, Vallés SL, Pascual M, Guerri C | title = Involvement of TLR4/type I IL-1 receptor signaling in the induction of inflammatory mediators and cell death induced by ethanol in cultured astrocytes | journal = Journal of Immunology | volume = 175 | issue = 10 | pages = 6893–6899 | date = November 2005 | pmid = 16272348 | doi = 10.4049/jimmunol.175.10.6893 | s2cid = 10682750 | doi-access = free }}</ref>
+Targeting TLR4 with agonists or antagonists, or modulating its downstream signaling pathways, may have a therapeutic potential in treating neurodegenerative diseases <ref>{{Cite journal |last=Wu |first=Linyu |last2=Xian |first2=Xiaohui |last3=Xu |first3=Guangyu |last4=Tan |first4=Zixuan |last5=Dong |first5=Fang |last6=Zhang |first6=Min |last7=Zhang |first7=Feng |date=2022-08-21 |title=Toll-Like Receptor 4: A Promising Therapeutic Target for Alzheimer’s Disease |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9420645/ |journal=Mediators of Inflammation |language=en |volume=2022 |pages=1–20 |doi=10.1155/2022/7924199 |issn=1466-1861}}</ref>. TLR4-specific antagonists could suppress neuroinflammation by reducing overproduction of inflammatory mediators and cytotoxins by glia. However, TLR4 antagonists could have adverse CNS effects by inhibiting phagocytosis by glia, reducing protein clearance, and interfering with myelination <ref>{{Cite journal |last=Leitner |first=Gunnar R. |last2=Wenzel |first2=Tyler J. |last3=Marshall |first3=Nick |last4=Gates |first4=Ellen J. |last5=Klegeris |first5=Andis |date=2019-10 |title=Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders |url=https://pubmed.ncbi.nlm.nih.gov/31580163/ |journal=Expert Opinion on Therapeutic Targets |volume=23 |issue=10 |pages=865–882 |doi=10.1080/14728222.2019.1676416 |issn=1744-7631 |pmid=31580163}}</ref>. Some studies showed that selective TLR4 agonists could be beneficial by upregulating the phagocytic activity of microglia, leading to enhanced clearance of damaged tissue and abnormal protein aggregates associated with several different CNS diseases. Repeated injections of MPL, at doses that are nonpyrogenic, were found to significantly improved AD-related pathology mice <ref>{{Cite journal |last=Michaud |first=Jean-Philippe |last2=Hallé |first2=Maxime |last3=Lampron |first3=Antoine |last4=Thériault |first4=Peter |last5=Préfontaine |first5=Paul |last6=Filali |first6=Mohammed |last7=Tribout-Jover |first7=Pascale |last8=Lanteigne |first8=Anne-Marie |last9=Jodoin |first9=Rachel |last10=Cluff |first10=Christopher |last11=Brichard |first11=Vincent |last12=Palmantier |first12=Rémi |last13=Pilorget |first13=Anthony |last14=Larocque |first14=Daniel |last15=Rivest |first15=Serge |date=2013-01-29 |title=Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer's disease-related pathology |url=https://pubmed.ncbi.nlm.nih.gov/23322736/ |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=110 |issue=5 |pages=1941–1946 |doi=10.1073/pnas.1215165110 |issn=1091-6490 |pmc=3562771 |pmid=23322736}}</ref>. MPL led to a significant reduction in Aβ load in the brain, as well as enhanced cognitive function. MPL induced a potent phagocytic response by microglia while triggering a moderate inflammatory reaction. However, adverse effects can be caused by TLR 4 agonists inducing secretion of inflammatory mediators. Studies therefore suggested that TLR4 agonists that selectively activate the TRIF signaling pathway could be highly beneficial in the treatment of neurodegenerative disorders by increasing glial cell phagocytic activity without significantly increasing glial cytokines and cytotoxins <ref>{{Cite journal |last=Leitner |first=Gunnar R. |last2=Wenzel |first2=Tyler J. |last3=Marshall |first3=Nick |last4=Gates |first4=Ellen J. |last5=Klegeris |first5=Andis |date=2019-10 |title=Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders |url=https://pubmed.ncbi.nlm.nih.gov/31580163/ |journal=Expert Opinion on Therapeutic Targets |volume=23 |issue=10 |pages=865–882 |doi=10.1080/14728222.2019.1676416 |issn=1744-7631 |pmid=31580163}}</ref>.
-High levels of TLR4 molecules and M2 [[tumor-associated macrophage]]s are associated with increased susceptibility to cancer growth in mice deprived of sleep.  Mice genetically modified so that they could not produce TLR4 molecules showed normal cancer growth.<ref name="pmid24448240">{{cite journal | vauthors = Hakim F, Wang Y, Zhang SX, Zheng J, Yolcu ES, Carreras A, Khalyfa A, Shirwan H, Almendros I, Gozal D | display-authors = 6 | title = Fragmented sleep accelerates tumor growth and progression through recruitment of tumor-associated macrophages and TLR4 signaling | journal = Cancer Research | volume = 74 | issue = 5 | pages = 1329–1337 | date = March 2014 | pmid = 24448240 | pmc = 4247537 | doi = 10.1158/0008-5472.CAN-13-3014 }}</ref>
 == Drugs targeting TLR4 ==
@@ Line 98: / Line 90: @@
 === Agonists ===
+Apart from LPS and its derivatives, up to 30 natural TLR4 agonists with diverse chemical structures have been postulated. However, besides DAMPs, the others have not demonstrated to be direct activators of TLR4 and could therefore act as chaperones for TLR4 or as promoters of LPS internalization <ref>{{Cite journal |last=Yang |first=Huan |last2=Wang |first2=Haichao |last3=Ju |first3=Zhongliang |last4=Ragab |first4=Ahmed A. |last5=Lundbäck |first5=Peter |last6=Long |first6=Wei |last7=Valdes-Ferrer |first7=Sergio I. |last8=He |first8=Mingzhu |last9=Pribis |first9=John P. |last10=Li |first10=Jianhua |last11=Lu |first11=Ben |last12=Gero |first12=Domokos |last13=Szabo |first13=Csaba |last14=Antoine |first14=Daniel J. |last15=Harris |first15=Helena E. |date=2015-01-05 |title=MD-2 is required for disulfide HMGB1–dependent TLR4 signaling |url=https://doi.org/10.1084/jem.20141318 |journal=Journal of Experimental Medicine |volume=212 |issue=1 |pages=5–14 |doi=10.1084/jem.20141318 |issn=1540-9538 |pmc=PMC4291531 |pmid=25559892}}</ref><ref>{{Cite journal |last=Manček‐Keber |first=Mateja |last2=Jerala |first2=Roman |date=2015-02 |title=Postulates for validating TLR4 agonists |url=https://onlinelibrary.wiley.com/doi/10.1002/eji.201444462 |journal=European Journal of Immunology |language=en |volume=45 |issue=2 |pages=356–370 |doi=10.1002/eji.201444462 |issn=0014-2980}}</ref><ref>{{Cite journal |last=Kim |first=Ho Min |last2=Kim |first2=You-Me |date=2018-10 |title=HMGB1: LPS Delivery Vehicle for Caspase-11-Mediated Pyroptosis |url=https://linkinghub.elsevier.com/retrieve/pii/S1074761318304369 |journal=Immunity |language=en |volume=49 |issue=4 |pages=582–584 |doi=10.1016/j.immuni.2018.09.021}}</ref>.
-{{div col|colwidth=20em}}
-* [[Buprenorphine]]<ref name="pmid19679181"/>
-* [[Carbamazepine]]<ref name="pmid20381591"/>
-* [[Ethanol]]<ref name="pmid21352907">{{cite journal | vauthors = Pascual M, Baliño P, Alfonso-Loeches S, Aragón CM, Guerri C | title = Impact of TLR4 on behavioral and cognitive dysfunctions associated with alcohol-induced neuroinflammatory damage | journal = Brain, Behavior, and Immunity | volume = 25 | issue = Suppl 1 | pages = S80–S91 | date = June 2011 | pmid = 21352907 | doi = 10.1016/j.bbi.2011.02.012 | s2cid = 205861788 }}</ref>
-* [[Fentanyl]]<ref name="pmid19679181"/>
-* [[Levorphanol]]<ref name="pmid19679181"/>
-* [[Lipopolysaccharide]]s (LPS)<ref name="pmid21193024">{{cite journal | vauthors = Kelley KW, Dantzer R | title = Alcoholism and inflammation: neuroimmunology of behavioral and mood disorders | journal = Brain, Behavior, and Immunity | volume = 25 | issue = Suppl 1 | pages = S13–S20 | date = June 2011 | pmid = 21193024 | pmc = 4068736 | doi = 10.1016/j.bbi.2010.12.013 }}</ref>
-* [[Methadone]]<ref name="pmid19679181"/>
-* [[Morphine]]<ref name="pmid19679181"/>
-* [[Oxcarbazepine]]<ref name="pmid20381591"/>
-* [[Oxycodone]]<ref name="pmid19679181"/>
-* [[Pethidine]]<ref name="pmid19679181"/>
-{{Div col end}}
-* [[AHCC]] (Active hexose correlated compound)<ref>{{cite journal | vauthors = Mallet JF, Graham É, Ritz BW, Homma K, Matar C | title = Active Hexose Correlated Compound (AHCC) promotes an intestinal immune response in BALB/c mice and in primary intestinal epithelial cell culture involving toll-like receptors TLR-2 and TLR-4 | journal = European Journal of Nutrition | volume = 55 | issue = 1 | pages = 139–146 | date = February 2016 | pmid = 25596849 | doi = 10.1007/s00394-015-0832-2 }}</ref>
-* Glucuronoxylomannan from [[Cryptococcus]]<ref name="pmid1629934">{{cite journal | vauthors = Harris SA, Solomon KR | title = Percutaneous penetration of 2,4-dichlorophenoxyacetic acid and 2,4-D dimethylamine salt in human volunteers | journal = Journal of Toxicology and Environmental Health | volume = 36 | issue = 3 | pages = 233–240 | date = July 1992 | pmid = 1629934 | doi = 10.1080/15287399209531634 }}</ref><ref name="pmid15593014">{{cite journal | vauthors = Monari C, Bistoni F, Casadevall A, Pericolini E, Pietrella D, Kozel TR, Vecchiarelli A | title = Glucuronoxylomannan, a microbial compound, regulates expression of costimulatory molecules and production of cytokines in macrophages | journal = The Journal of Infectious Diseases | volume = 191 | issue = 1 | pages = 127–137 | date = January 2005 | pmid = 15593014 | doi = 10.1086/426511 | doi-access = free }}</ref>
-* [[Morphine-3-glucuronide]] (inactive at opioid receptors, so selective for TLR4 activation)<ref name="pmid19833175" /><ref name="pmid19679181" />
-* [[Tapentadol]] (combined full μ-opioid receptor agonist and norepinephrine reuptake inhibitor)
-* "Unnatural" isomers such as [[(%2B)-Morphine|(+)-morphine]] activate TLR4 but lack opioid receptor activity,<ref name="pmid19762094" /> although (+)-morphine also shows activity as a [[sigma receptor]] agonist.<ref name="pmid17617400">{{cite journal | vauthors = Wu HE, Hong JS, Tseng LF | title = Stereoselective action of (+)-morphine over (-)-morphine in attenuating the (-)-morphine-produced antinociception via the naloxone-sensitive sigma receptor in the mouse | journal = European Journal of Pharmacology | volume = 571 | issue = 2–3 | pages = 145–151 | date = October 2007 | pmid = 17617400 | pmc = 2080825 | doi = 10.1016/j.ejphar.2007.06.012 }}</ref>
 === Antagonists ===

v t e Proteins: clusters of differentiation (see also list of human clusters of differentiation)
1–50	CD1 a-c 1A 1B 1D 1E CD2 CD3 γ δ ε CD4 CD5 CD6 CD7 CD8 a CD9 CD10 CD11 a b c d CD13 CD14 CD15 CD16 A B CD18 CD19 CD20 CD21 CD22 CD23 CD24 CD25 CD26 CD27 CD28 CD29 CD30 CD31 CD32 A B CD33 CD34 CD35 CD36 CD37 CD38 CD39 CD40 CD41 CD42 a b c d CD43 CD44 CD45 CD46 CD47 CD48 CD49 a b c d e f CD50
51–100	CD51 CD52 CD53 CD54 CD55 CD56 CD57 CD58 CD59 CD61 CD62 E L P CD63 CD64 A B C CD66 a b c d e f CD68 CD69 CD70 CD71 CD72 CD73 CD74 CD78 CD79 a b CD80 CD81 CD82 CD83 CD84 CD85 a d e h j k CD86 CD87 CD88 CD89 CD90 CD91 - CD92 CD93 CD94 CD95 CD96 CD97 CD98 CD99 CD100
101–150	CD101 CD102 CD103 CD104 CD105 CD106 CD107 a b CD108 CD109 CD110 CD111 CD112 CD113 CD114 CD115 CD116 CD117 CD118 CD119 CD120 a b CD121 a b CD122 CD123 CD124 CD125 CD126 CD127 CD129 CD130 CD131 CD132 CD133 CD134 CD135 CD136 CD137 CD138 CD140b CD141 CD142 CD143 CD144 CD146 CD147 CD148 CD150
151–200	CD151 CD152 CD153 CD154 CD155 CD156 a b c CD157 CD158 (a d e i k) CD159 a c CD160 CD161 CD162 CD163 CD164 CD166 CD167 a b CD168 CD169 CD170 CD171 CD172 a b g CD174 CD177 CD178 CD179 a b CD180 CD181 CD182 CD183 CD184 CD185 CD186 CD191 CD192 CD193 CD194 CD195 CD196 CD197 CDw198 CDw199 CD200
201–250	CD201 CD202b CD204 CD205 CD206 CD207 CD208 CD209 CDw210 a b CD212 CD213a 1 2 CD217 CD218 (a b) CD220 CD221 CD222 CD223 CD224 CD225 CD226 CD227 CD228 CD229 CD230 CD233 CD234 CD235 a b CD236 CD238 CD239 CD240CE CD240D CD241 CD243 CD244 CD246 CD247 - CD248 CD249
251–300	CD252 CD253 CD254 CD256 CD257 CD258 CD261 CD262 CD263 CD264 CD265 CD266 CD267 CD268 CD269 CD271 CD272 CD273 CD274 CD275 CD276 CD278 CD279 CD280 CD281 CD282 CD283 CD284 CD286 CD288 CD289 CD290 CD292 CDw293 CD294 CD295 CD297 CD298 CD299
301–350	CD300A CD301 CD302 CD303 CD304 CD305 CD306 CD307 CD309 CD312 CD314 CD315 CD316 CD317 CD318 CD320 CD321 CD322 CD324 CD325 CD326 CD327 CD328 CD329 CD331 CD332 CD333 CD334 CD335 CD336 CD337 CD338 CD339 CD340 CD344 CD349 CD350

v t e Signaling pathway: TLR signaling pathway
TLRs	TLR1 TLR2 TLR3 TLR4 TLR5 TLR6 TLR7 TLR8 TLR9 TLR10 TLR11 TLR12 TLR13
Other receptors	CD14 LBP MD2
Downstream signalling	IRAK1 IRAK2 IRAK3 IRAK4 IRF3 MAP3K7 MYD88 TAB1 TICAM1 TIRAP TOLLIP TRAF6