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
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; ; right lung; ; gallbladder; ; bone marrow cells; ; subcutaneous adipose tissue;
	Top expressed in
	aortic valve; ; ascending aorta; ; epithelium of stomach; ; cervix; ; mucous cell of stomach; ; sciatic nerve; ; white adipose tissue; ; calvaria; ; carotid body; ; seminal vesicula;
	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 18:57, 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]. DAMPs can activate TLR4 in non-infectious conditions to induce tissue repair and the activation of mainly 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, in addition to the lipid A domain, the polysaccharide moiety plays an important role in the binding and activation of the LPS molecules as the lipid A moiety alone was demonstrated to be significantly 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 ^[28]^[29]. The molecular structure of TLR4 ligands (in particular LPS), 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.^[30] 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.^[31] 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 ^[32]^[33]^[34].

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 ^[35]. 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 ^[36]^[37]^[38]^[39].

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 ^[40]^[41]. 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 ^[42]^[43]. 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 ^[44]^[45]^[46]^[47]. 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 ^[48]. 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 ^[49].

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 ^[50]^[51]^[52].

Evolutionary history and polymorphism

TLR4 originated when TLR2 and TLR4 diverged about 500 million years ago near the beginning of vertebrate evolution.^[53] 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 ^[54]. 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 ^[55]^[56]. 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 ^[56]^[57].

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 ^[58]. 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 ^[59]^[60] 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 ^[61].

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 ^[62]. 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 ^[63]. 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 ^[64]. 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 ^[65].

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 ^[66]^[67].

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 ^[68]. Later, Dr William Coley showed the therapeutic efficacy of a mixed bacterial vaccine, so-called “Coley’s toxin”, to human cancer ^[69]. 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 ^[70]. 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) ^[71]. 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.^[72]

Purified LPS also showed potent anti-tumor efficacy as systemic therapeutic agents in several tumor models.^[73] ^[74]^[75]. 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 ^[76].

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 ^[77]. 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 ^[78], and potent adjuvant activity in phase 2 trials in combination with pembrolizumab in patients with follicular lymphoma ^[79]^[80].

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 ^[81]. 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 ^[82].

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 ^[83]^[84]^[85]. Several studies showed that this is mediated by the misuse of DAMP signaling by tumor cells ^[86]^[87]^[88].

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) ^[89]. 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 ^[90].

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) ^[91].

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 ^[92]. Microglia are representatives of the mononuclear phagocyte system in the brain, and TLR4 activation regulates some of their functions, such as phagocytic activity ^[93]^[94].

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 ^[95].

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 ^[96]^[97]. 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 ^[98]. 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 ^[99]^[100]^[101]. Neuronal death is accompanied by the release of DAMPs into the extracellular space, which can then further activate TLR4, aggravating neuroinflammation ^[102]. 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 ^[103]. In AD patients, the serum levels of S100B are also intimately related to the severity of the disease ^[104]. 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 ^[105].

Targeting TLR4 with agonists or antagonists, or modulating its downstream signaling pathways, may have a therapeutic potential in treating neurodegenerative diseases ^[106]. 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 ^[107]. 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 ^[108]. 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 ^[109].

Drugs targeting TLR4

TLR4 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,^[110]^[111] and in the emergence of side-effects such as hyperalgesia and allodynia that can become a problem following extended use of opioid drugs.^[112]^[113] 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,^[114]^[115] 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.^[116]^[117] 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.^[118]^[117]^[119] This may also be the mechanism behind the beneficial effect of ultra-low dose naltrexone on opioid analgesia.^[120]

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).^[121] 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.^[122]

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 ^[123]^[124]^[125].

Antagonists

As of 2020, there were no specific TLR4 antagonists approved as drugs.^[126]

Amitriptyline^[127]
Cyclobenzaprine^[127]
Eritoran^[128]
Ketotifen^[127]
Imipramine^[127]
Mianserin^[127]
Ibudilast^[129]
Pinocembrin^[130]
Resatorvid^[131]
M62812
Naloxone^[132]
(+)-Naloxone ("unnatural" isomer, lacks opioid receptor affinity so selective for TLR4 inhibition)^[117]
Naltrexone^[132]
(+)-Naltrexone^[132]
LPS-RS^[132]
Propentofylline^{[citation needed]}
Pentoxifylline^[133] (and downregulate TLR4 expression^[134])
Tapentadol (mixed agonist/antagonist)
TLR4-IN-C34^[135]
Palmitoylethanolamide^[136]

References

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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

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@@ Line 4: / Line 4: @@
 '''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''' 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 | pages = 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 | series = Advances in Experimental Medicine and Biology |volume=417 |pages=145–159 | veditors = Ricciardi-Castagnoli P |place=Boston, MA |publisher=Springer US |doi=10.1007/978-1-4757-9966-8_25 | pmid = 9286353 |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>
-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>.
+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 | 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 name=":0">{{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 name=":1">{{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 name=":2">{{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 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 |last1=Molteni |first1=Monica |last2=Gemma |first2=Sabrina |last3=Rossetti |first3=Carlo |date=2016 |title=The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation |journal=Mediators of Inflammation |volume=2016 |pages=6978936 |doi=10.1155/2016/6978936 |doi-access=free |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 |last1=Molteni |first1=Monica |last2=Gemma |first2=Sabrina |last3=Rossetti |first3=Carlo |date=2016 |title=The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation |journal=Mediators of Inflammation |volume=2016 |pages=6978936 |doi=10.1155/2016/6978936 |doi-access=free |issn=0962-9351 |pmc=4887650 |pmid=27293318}}</ref>.
+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 | vauthors = Molteni M, Gemma S, Rossetti C | title = The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation | journal = Mediators of Inflammation | volume = 2016 | pages = 6978936 | date = 2016 | pmid = 27293318 | pmc = 4887650 | doi = 10.1155/2016/6978936 | doi-access = free }}</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 | vauthors = Molteni M, Gemma S, Rossetti C | title = The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation | journal = Mediators of Inflammation | volume = 2016 | pages = 6978936 | date = 2016 | pmid = 27293318 | pmc = 4887650 | doi = 10.1155/2016/6978936 | doi-access = free }}</ref>.
-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 |last1=Roh |first1=Jong Seong |last2=Sohn |first2=Dong Hyun |date=2018-08-13 |title=Damage-Associated Molecular Patterns in Inflammatory Diseases |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 |last1=Jang |first1=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=December 2020 |title=Interactions between tumor-derived proteins and Toll-like receptors |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 can activate TLR4 in non-infectious conditions to induce tissue repair and the activation of mainly 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).
+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 | vauthors = Roh JS, Sohn DH | title = Damage-Associated Molecular Patterns in Inflammatory Diseases | journal = Immune Network | volume = 18 | issue = 4 | pages = e27 | date = August 2018 | pmid = 30181915 | pmc = 6117512 | doi = 10.4110/in.2018.18.e27 }}</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>. DAMPs can activate TLR4 in non-infectious conditions to induce tissue repair and the activation of mainly 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).
-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 |last1=Tsukamoto |first1=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=June 2018 |title=Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent Toll-like receptor 4 internalization and LPS-induced TBK1–IKKϵ–IRF3 axis activation |journal=Journal of Biological Chemistry |language=en |volume=293 |issue=26 |pages=10186–10201 |doi=10.1074/jbc.M117.796631 |doi-access=free |pmc=6028956 |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.
+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 | vauthors = 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 | display-authors = 6 | title = Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent Toll-like receptor 4 internalization and LPS-induced TBK1-IKKϵ-IRF3 axis activation | journal = The Journal of Biological Chemistry | volume = 293 | issue = 26 | pages = 10186–10201 | date = June 2018 | pmid = 29760187 | pmc = 6028956 | doi = 10.1074/jbc.M117.796631 | doi-access = free }}</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.
-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 |last1=Park |first1=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=April 2009 |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 |pmid=19252480 |bibcode=2009Natur.458.1191P |s2cid=4396446 |issn=0028-0836}}</ref><ref>{{Cite journal |last1=Park |first1=Beom Seok |last2=Lee |first2=Jie-Oh |date=2013-12-06 |title=Recognition of lipopolysaccharide pattern by TLR4 complexes |journal=Experimental & Molecular Medicine |language=en |volume=45 |issue=12 |pages=e66 |doi=10.1038/emm.2013.97 |issn=2092-6413 |pmc=3880462 |pmid=24310172}}</ref>.
+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 | vauthors = Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO | title = The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex | journal = Nature | volume = 458 | issue = 7242 | pages = 1191–1195 | date = April 2009 | pmid = 19252480 | doi = 10.1038/nature07830 | s2cid = 4396446 | bibcode = 2009Natur.458.1191P }}</ref><ref>{{cite journal | vauthors = Park BS, Lee JO | title = Recognition of lipopolysaccharide pattern by TLR4 complexes | journal = Experimental & Molecular Medicine | volume = 45 | issue = 12 | pages = e66 | date = December 2013 | pmid = 24310172 | pmc = 3880462 | doi = 10.1038/emm.2013.97 }}</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 |last1=Steimle |first1=Alex |last2=Autenrieth |first2=Ingo B. |last3=Frick |first3=Julia-Stefanie |date=August 2016 |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 |last1=Park |first1=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=April 2009 |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 |pmid=19252480 |bibcode=2009Natur.458.1191P |s2cid=4396446 |issn=0028-0836}}</ref><ref>{{Cite journal |last1=Kelley |first1=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=3552104 |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 |last1=Muroi |first1=Masashi |last2=Tanamoto |first2=Ken-Ichi |date=November 2002 |title=The polysaccharide portion plays an indispensable role in Salmonella lipopolysaccharide-induced activation of NF-kappaB through human toll-like receptor 4 |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|pmc=130318 }}</ref>. However, in addition to the lipid A domain, the polysaccharide moiety plays an important role in the binding and activation of the LPS molecules as the lipid A moiety alone was demonstrated to be significantly less active than the full LPS molecule <ref>{{Cite journal |last1=Cavaillon |first1=J M |last2=Fitting |first2=C |last3=Caroff |first3=M |last4=Haeffner-Cavaillon |first4=N |date=March 1989 |title=Dissociation of cell-associated interleukin-1 (IL-1) and IL-1 release induced by lipopolysaccharide and lipid A |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=313178 |pmid=2537258}}</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 | vauthors = Steimle A, Autenrieth IB, Frick JS | title = Structure and function: Lipid A modifications in commensals and pathogens | journal = International Journal of Medical Microbiology | volume = 306 | issue = 5 | pages = 290–301 | date = August 2016 | pmid = 27009633 | doi = 10.1016/j.ijmm.2016.03.001 }}</ref>. Structural determinants of this phenomenon are found in the TLR4/MD-2 complex and also in CD14 protein <ref>{{cite journal | vauthors = Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO | title = The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex | journal = Nature | volume = 458 | issue = 7242 | pages = 1191–1195 | date = April 2009 | pmid = 19252480 | doi = 10.1038/nature07830 | s2cid = 4396446 | bibcode = 2009Natur.458.1191P }}</ref><ref>{{cite journal | vauthors = Kelley SL, Lukk T, Nair SK, Tapping RI | title = The crystal structure of human soluble CD14 reveals a bent solenoid with a hydrophobic amino-terminal pocket | journal = Journal of Immunology | volume = 190 | issue = 3 | pages = 1304–1311 | date = February 2013 | pmid = 23264655 | pmc = 3552104 | doi = 10.4049/jimmunol.1202446 }}</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 | vauthors = Muroi M, Tanamoto K | title = The polysaccharide portion plays an indispensable role in Salmonella lipopolysaccharide-induced activation of NF-kappaB through human toll-like receptor 4 | journal = Infection and Immunity | volume = 70 | issue = 11 | pages = 6043–6047 | date = November 2002 | pmid = 12379680 | pmc = 130318 | doi = 10.1128/IAI.70.11.6043-6047.2002 }}</ref>. However, in addition to the lipid A domain, the polysaccharide moiety plays an important role in the binding and activation of the LPS molecules as the lipid A moiety alone was demonstrated to be significantly less active than the full LPS molecule <ref>{{cite journal | vauthors = Cavaillon JM, Fitting C, Caroff M, Haeffner-Cavaillon N | title = Dissociation of cell-associated interleukin-1 (IL-1) and IL-1 release induced by lipopolysaccharide and lipid A | journal = Infection and Immunity | volume = 57 | issue = 3 | pages = 791–797 | date = March 1989 | pmid = 2537258 | pmc = 313178 | doi = 10.1128/iai.57.3.791-797.1989 }}</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 |last1=Shen |first1=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 |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 |last1=Shen |first1=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 |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.
+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 | vauthors = Shen H, Tesar BM, Walker WE, Goldstein DR | title = Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation | journal = Journal of Immunology | volume = 181 | issue = 3 | pages = 1849–1858 | date = August 2008 | pmid = 18641322 | pmc = 2507878 | doi = 10.4049/jimmunol.181.3.1849 }}</ref><ref>{{cite journal | vauthors = Shen H, Tesar BM, Walker WE, Goldstein DR | title = Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation | journal = Journal of Immunology | volume = 181 | issue = 3 | pages = 1849–1858 | date = August 2008 | pmid = 18641322 | pmc = 2507878 | doi = 10.4049/jimmunol.181.3.1849 }}</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.
-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 <ref>{{Cite journal |last1=Shen |first1=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://journals.aai.org/jimmunol/article/181/3/1849/38323/Dual-Signaling-of-MyD88-and-TRIF-Is-Critical-for |journal=The Journal of Immunology |language=en |volume=181 |issue=3 |pages=1849–1858 |doi=10.4049/jimmunol.181.3.1849 |issn=0022-1767 |pmc=2507878 |pmid=18641322}}</ref><ref>{{Cite journal |last1=Nakayama |first1=Masanori |last2=Niki |first2=Yasuo |last3=Kawasaki |first3=Toshiki |last4=Takeda |first4=Yuki |last5=Ikegami |first5=Hiroyasu |last6=Toyama |first6=Yoshiaki |last7=Miyamoto |first7=Takeshi |date=2013-10-16 |title=IL-32-PAR2 axis is an innate immunity sensor providing alternative signaling for LPS-TRIF axis |journal=Scientific Reports |language=en |volume=3 |issue=1 |page=2960 |doi=10.1038/srep02960 |issn=2045-2322 |pmc=3797434 |pmid=24129891|bibcode=2013NatSR...3E2960N }}</ref>. The molecular structure of TLR4 ligands (in particular LPS), 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 depedent signaling pathway of TLR4.]]
+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 <ref>{{cite journal | vauthors = Shen H, Tesar BM, Walker WE, Goldstein DR | title = Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation | journal = Journal of Immunology | volume = 181 | issue = 3 | pages = 1849–1858 | date = August 2008 | pmid = 18641322 | pmc = 2507878 | doi = 10.4049/jimmunol.181.3.1849 }}</ref><ref>{{cite journal | vauthors = Nakayama M, Niki Y, Kawasaki T, Takeda Y, Ikegami H, Toyama Y, Miyamoto T | title = IL-32-PAR2 axis is an innate immunity sensor providing alternative signaling for LPS-TRIF axis | journal = Scientific Reports | volume = 3 | issue = 1 | pages = 2960 | date = October 2013 | pmid = 24129891 | pmc = 3797434 | doi = 10.1038/srep02960 | bibcode = 2013NatSR...3E2960N }}</ref>. The molecular structure of TLR4 ligands (in particular LPS), 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 depedent signaling pathway of TLR4.]]
 === 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">{{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 |last1=Meissner |first1=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 |pmid=23620052 |bibcode=2013Sci...340..475M |s2cid=40513139 |issn=0036-8075}}</ref><ref>{{Cite journal |last1=Kawai |first1=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 |pmid=11698465 |issn=0022-1767}}</ref><ref>{{Cite journal |last1=Chanteux |first1=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 |journal=Respiratory Research |volume=8 |issue=1 |pages=71 |doi=10.1186/1465-9921-8-71 |doi-access=free |issn=1465-993X |pmc=2080632 |pmid=17916230}}</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 | 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> 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 | vauthors = Meissner F, Scheltema RA, Mollenkopf HJ, Mann M | title = Direct proteomic quantification of the secretome of activated immune cells | journal = Science | volume = 340 | issue = 6131 | pages = 475–478 | date = April 2013 | pmid = 23620052 | doi = 10.1126/science.1232578 | s2cid = 40513139 | bibcode = 2013Sci...340..475M }}</ref><ref>{{cite journal | vauthors = Kawai T, Takeuchi O, Fujita T, Inoue J, Mühlradt PF, Sato S, Hoshino K, Akira S | display-authors = 6 | 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 | journal = Journal of Immunology | volume = 167 | issue = 10 | pages = 5887–5894 | date = November 2001 | pmid = 11698465 | doi = 10.4049/jimmunol.167.10.5887 }}</ref><ref>{{cite journal | vauthors = Chanteux H, Guisset AC, Pilette C, Sibille Y | title = LPS induces IL-10 production by human alveolar macrophages via MAPKinases- and Sp1-dependent mechanisms | journal = Respiratory Research | volume = 8 | issue = 1 | pages = 71 | date = October 2007 | pmid = 17916230 | pmc = 2080632 | doi = 10.1186/1465-9921-8-71 | doi-access = free }}</ref>.
 === 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 |last1=Ciesielska |first1=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 |journal=Cellular and Molecular Life Sciences |language=en |volume=78 |issue=4 |pages=1233–1261 |doi=10.1007/s00018-020-03656-y |pmid=33057840 |pmc=7904555 |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 |last1=Meissner |first1=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 |pmid=23620052 |bibcode=2013Sci...340..475M |s2cid=40513139 |issn=0036-8075}}</ref><ref>{{Cite journal |last1=Kawai |first1=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 |pmid=11698465 |issn=0022-1767}}</ref><ref>{{Cite journal |last1=Chanteux |first1=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 |journal=Respiratory Research |volume=8 |issue=1 |pages=71 |doi=10.1186/1465-9921-8-71 |doi-access=free |issn=1465-993X |pmc=2080632 |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>.
+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 | 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>. 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 | vauthors = Meissner F, Scheltema RA, Mollenkopf HJ, Mann M | title = Direct proteomic quantification of the secretome of activated immune cells | journal = Science | volume = 340 | issue = 6131 | pages = 475–478 | date = April 2013 | pmid = 23620052 | doi = 10.1126/science.1232578 | s2cid = 40513139 | bibcode = 2013Sci...340..475M }}</ref><ref>{{cite journal | vauthors = Kawai T, Takeuchi O, Fujita T, Inoue J, Mühlradt PF, Sato S, Hoshino K, Akira S | display-authors = 6 | 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 | journal = Journal of Immunology | volume = 167 | issue = 10 | pages = 5887–5894 | date = November 2001 | pmid = 11698465 | doi = 10.4049/jimmunol.167.10.5887 }}</ref><ref>{{cite journal | vauthors = Chanteux H, Guisset AC, Pilette C, Sibille Y | title = LPS induces IL-10 production by human alveolar macrophages via MAPKinases- and Sp1-dependent mechanisms | journal = Respiratory Research | volume = 8 | issue = 1 | pages = 71 | date = October 2007 | pmid = 17916230 | pmc = 2080632 | doi = 10.1186/1465-9921-8-71 | doi-access = free }}</ref><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>.
 == 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 (protein)|CD40]], [[CD80]] and [[CD86]] on the cell surface which are required for antigen presentation for T lymphocytes <ref>{{Cite journal |last1=Lien |first1=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=February 2000 |title=Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide |journal=The Journal of Clinical Investigation |volume=105 |issue=4 |pages=497–504 |doi=10.1172/JCI8541 |issn=0021-9738 |pmid=10683379|pmc=289161 }}</ref><ref>{{Cite journal |last1=Shetab Boushehri |first1=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 |pmid=30226786 |s2cid=52297047 |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 |last1=Shetab Boushehri |first1=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 |pmid=30226786 |s2cid=52297047 |issn=1543-8384}}</ref><ref>{{Cite journal |last1=Shen |first1=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 |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 |last1=Kaisho |first1=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 |last1=Hoebe |first1=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=December 2003 |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 |pmid=14625548 |s2cid=8505015 |issn=1529-2916}}</ref><ref>{{Cite journal |last1=Shen |first1=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 |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 |last1=Trombetta |first1=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 |pmid=12610307 |s2cid=46594244 |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 |last1=Turley |first1=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 |pmid=10775112 |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 |last1=Nair-Gupta |first1=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=July 2014 |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=4212008 |pmid=25083866}}</ref>.
+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 | vauthors = 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 | display-authors = 6 | title = Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide | journal = The Journal of Clinical Investigation | volume = 105 | issue = 4 | pages = 497–504 | date = February 2000 | pmid = 10683379 | pmc = 289161 | doi = 10.1172/JCI8541 }}</ref><ref>{{cite journal | vauthors = Shetab Boushehri MA, Lamprecht A | title = TLR4-Based Immunotherapeutics in Cancer: A Review of the Achievements and Shortcomings | journal = Molecular Pharmaceutics | volume = 15 | issue = 11 | pages = 4777–4800 | date = November 2018 | pmid = 30226786 | doi = 10.1021/acs.molpharmaceut.8b00691 | s2cid = 52297047 }}</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 | vauthors = Shetab Boushehri MA, Lamprecht A | title = TLR4-Based Immunotherapeutics in Cancer: A Review of the Achievements and Shortcomings | journal = Molecular Pharmaceutics | volume = 15 | issue = 11 | pages = 4777–4800 | date = November 2018 | pmid = 30226786 | doi = 10.1021/acs.molpharmaceut.8b00691 | s2cid = 52297047 }}</ref><ref>{{cite journal | vauthors = Shen H, Tesar BM, Walker WE, Goldstein DR | title = Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation | journal = Journal of Immunology | volume = 181 | issue = 3 | pages = 1849–1858 | date = August 2008 | pmid = 18641322 | pmc = 2507878 | doi = 10.4049/jimmunol.181.3.1849 }}</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 | vauthors = Kaisho T, Takeuchi O, Kawai T, Hoshino K, Akira S | title = Endotoxin-induced maturation of MyD88-deficient dendritic cells | journal = Journal of Immunology | volume = 166 | issue = 9 | pages = 5688–5694 | date = May 2001 | pmid = 11313410 | doi = 10.4049/jimmunol.166.9.5688 }}</ref><ref>{{cite journal | vauthors = Hoebe K, Janssen EM, Kim SO, Alexopoulou L, Flavell RA, Han J, Beutler B | title = Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways | journal = Nature Immunology | volume = 4 | issue = 12 | pages = 1223–1229 | date = December 2003 | pmid = 14625548 | doi = 10.1038/ni1010 | s2cid = 8505015 }}</ref><ref>{{cite journal | vauthors = Shen H, Tesar BM, Walker WE, Goldstein DR | title = Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation | journal = Journal of Immunology | volume = 181 | issue = 3 | pages = 1849–1858 | date = August 2008 | pmid = 18641322 | pmc = 2507878 | doi = 10.4049/jimmunol.181.3.1849 }}</ref><ref>{{cite journal | vauthors = Trombetta ES, Ebersold M, Garrett W, Pypaert M, Mellman I | title = Activation of lysosomal function during dendritic cell maturation | journal = Science | volume = 299 | issue = 5611 | pages = 1400–1403 | date = February 2003 | pmid = 12610307 | doi = 10.1126/science.1080106 | s2cid = 46594244 }}</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 | vauthors = Turley SJ, Inaba K, Garrett WS, Ebersold M, Unternaehrer J, Steinman RM, Mellman I | title = Transport of peptide-MHC class II complexes in developing dendritic cells | journal = Science | volume = 288 | issue = 5465 | pages = 522–527 | date = April 2000 | pmid = 10775112 | doi = 10.1126/science.288.5465.522 }}</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 | vauthors = 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 | display-authors = 6 | title = TLR signals induce phagosomal MHC-I delivery from the endosomal recycling compartment to allow cross-presentation | journal = Cell | volume = 158 | issue = 3 | pages = 506–521 | date = July 2014 | pmid = 25083866 | pmc = 4212008 | doi = 10.1016/j.cell.2014.04.054 }}</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 |last1=Paavonen |first1=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=April 2007 |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|s2cid=35472093 }}</ref><ref>{{Cite journal |last1=Garçon |first1=Nathalie |last2=Di Pasquale |first2=Alberta |date=2017-01-02 |title=From discovery to licensure, the Adjuvant System story |journal=Human Vaccines & Immunotherapeutics |language=en |volume=13 |issue=1 |pages=19–33 |doi=10.1080/21645515.2016.1225635 |issn=2164-5515 |pmc=5287309 |pmid=27636098}}</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 | vauthors = 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, Limson GA, Dionne M, Quint W, Spiessens B, Peeters P, Struyf F, Wieting SL, Lehtinen MO, Dubin G | display-authors = 6 | 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 | journal = Lancet | volume = 369 | issue = 9580 | pages = 2161–2170 | date = June 2007 | pmid = 17602732 | doi = 10.1016/S0140-6736(07)60946-5 }}</ref><ref>{{cite journal | vauthors = Kundi M | title = New hepatitis B vaccine formulated with an improved adjuvant system | journal = Expert Review of Vaccines | volume = 6 | issue = 2 | pages = 133–140 | date = April 2007 | pmid = 17408363 | doi = 10.1586/14760584.6.2.133 | s2cid = 35472093 }}</ref><ref>{{cite journal | vauthors = Garçon N, Di Pasquale A | title = From discovery to licensure, the Adjuvant System story | journal = Human Vaccines & Immunotherapeutics | volume = 13 | issue = 1 | pages = 19–33 | date = January 2017 | pmid = 27636098 | pmc = 5287309 | doi = 10.1080/21645515.2016.1225635 }}</ref>.
 == 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 |last1=Noreen |first1=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=March 2012 |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|s2cid=9500302 }}</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 |last1=Long |first1=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 |journal=PLOS ONE |language=en |volume=9 |issue=4 |pages=e93550 |doi=10.1371/journal.pone.0093550 |doi-access=free |issn=1932-6203 |pmc=3973565 |pmid=24695807|bibcode=2014PLoSO...993550L }}</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 |last1=Ohto |first1=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 |journal=The Journal of Biological Chemistry |volume=287 |issue=48 |pages=40611–40617 |doi=10.1074/jbc.M112.404608 |doi-access=free |issn=0021-9258 |pmc=3504774 |pmid=23055527}}</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 | vauthors = Noreen M, Shah MA, Mall SM, Choudhary S, Hussain T, Ahmed I, Jalil SF, Raza MI | display-authors = 6 | title = TLR4 polymorphisms and disease susceptibility | journal = Inflammation Research | volume = 61 | issue = 3 | pages = 177–188 | date = March 2012 | pmid = 22277994 | doi = 10.1007/s00011-011-0427-1 | s2cid = 9500302 }}</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 | vauthors = Long H, O'Connor BP, Zemans RL, Zhou X, Yang IV, Schwartz DA | title = The Toll-like receptor 4 polymorphism Asp299Gly but not Thr399Ile influences TLR4 signaling and function | journal = PloS One | volume = 9 | issue = 4 | pages = e93550 | date = 2014-04-02 | pmid = 24695807 | pmc = 3973565 | doi = 10.1371/journal.pone.0093550 | doi-access = free | bibcode = 2014PLoSO...993550L }}</ref><ref name="pmid22474023">{{cite journal | vauthors = Figueroa L, Xiong Y, Song C, Piao W, Vogel SN, Medvedev AE | title = The Asp299Gly polymorphism alters TLR4 signaling by interfering with recruitment of MyD88 and TRIF | journal = Journal of Immunology  | location = Baltimore | volume = 188 | issue = 9 | pages = 4506–15 | date = May 2012 | pmid = 22474023 | pmc = 3531971 | doi = 10.4049/jimmunol.1200202 }}</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 | vauthors = Ohto U, Yamakawa N, Akashi-Takamura S, Miyake K, Shimizu T | title = Structural analyses of human Toll-like receptor 4 polymorphisms D299G and T399I | journal = The Journal of Biological Chemistry | volume = 287 | issue = 48 | pages = 40611–40617 | date = November 2012 | pmid = 23055527 | pmc = 3504774 | doi = 10.1074/jbc.M112.404608 | doi-access = free }}</ref>.
 == Clinical significance==
@@ Line 50: / Line 50: @@
 === 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 <ref>{{Cite journal |last1=Akira |first1=Shizuo |last2=Takeda |first2=Kiyoshi |date=July 2004 |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 |last1=Molteni |first1=Monica |last2=Gemma |first2=Sabrina |last3=Rossetti |first3=Carlo |date=2016 |title=The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation |journal=Mediators of Inflammation |language=en |volume=2016 |pages=1–9 |doi=10.1155/2016/6978936 |doi-access=free |pmid=27293318|pmc=4887650 }}</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 |last1=Netea |first1=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|s2cid=24438756 }}</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 | vauthors = Akira S, Takeda K | title = Toll-like receptor signalling | journal = Nature Reviews. Immunology | volume = 4 | issue = 7 | pages = 499–511 | date = July 2004 | pmid = 15229469 | doi = 10.1038/nri1391 }}</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 | vauthors = Molteni M, Gemma S, Rossetti C | title = The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation | journal = Mediators of Inflammation | volume = 2016 | pages = 6978936 | date = 2016 | pmid = 27293318 | pmc = 4887650 | doi = 10.1155/2016/6978936 | doi-access = free }}</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 | 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|''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 | vauthors = Netea MG, Wijmenga C, O'Neill LA | title = Genetic variation in Toll-like receptors and disease susceptibility | journal = Nature Immunology | volume = 13 | issue = 6 | pages = 535–542 | date = May 2012 | pmid = 22610250 | doi = 10.1038/ni.2284 | s2cid = 24438756 }}</ref>.
 === In cancer ===
@@ Line 56: / Line 56: @@
 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 <ref>{{Cite journal |last1=Chettab |first1=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 |journal=Frontiers in Immunology |volume=14 |pages=1066402 |doi=10.3389/fimmu.2023.1066402 |doi-access=free |issn=1664-3224 |pmid=37223101|pmc=10200957 }}</ref><ref>{{Cite journal |last1=Richert |first1=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 |journal=Cancers |volume=15 |issue=18 |pages=4635 |doi=10.3390/cancers15184635 |doi-access=free |issn=2072-6694 |pmid=37760603|pmc=10526955 }}</ref>.
+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 | vauthors = 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, Caroff M, Kerzerho J, Dumontet C | display-authors = 6 | title = A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models | journal = Frontiers in Immunology | volume = 14 | pages = 1066402 | date = 2023 | pmid = 37223101 | pmc = 10200957 | doi = 10.3389/fimmu.2023.1066402 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Richert I, Berchard P, Abbes L, Novikov A, Chettab K, Vandermoeten A, Dumontet C, Karanian M, Kerzerho J, Caroff M, Blay JY, Dutour A | display-authors = 6 | title = A TLR4 Agonist Induces Osteosarcoma Regression by Inducing an Antitumor Immune Response and Reprogramming M2 Macrophages to M1 Macrophages | journal = Cancers | volume = 15 | issue = 18 | pages = 4635 | date = September 2023 | pmid = 37760603 | pmc = 10526955 | doi = 10.3390/cancers15184635 | doi-access = free }}</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 |last1=Maruyama |first1=Kouji |last2=Selmani |first2=Zohair |last3=Ishii |first3=Hidee |last4=Yamaguchi |first4=Ken |date=March 2011 |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|bibcode=1992Natur.357...11S |s2cid=4265230 }}</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 |last1=Tsuji |first1=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=December 2000 |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 |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=97794 |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 |last1=Ryoma |first1=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>.
+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 | vauthors = Maruyama K, Selmani Z, Ishii H, Yamaguchi K | title = Innate immunity and cancer therapy | journal = International Immunopharmacology | volume = 11 | issue = 3 | pages = 350–357 | date = March 2011 | pmid = 20955832 | doi = 10.1016/j.intimp.2010.09.012 }}</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 | vauthors = Starnes CO | title = Coley's toxins in perspective | journal = Nature | volume = 357 | issue = 6373 | pages = 11–12 | date = May 1992 | pmid = 1574121 | doi = 10.1038/357011a0 | s2cid = 4265230 | bibcode = 1992Natur.357...11S }}</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 | vauthors = Tsuji S, Matsumoto M, Takeuchi O, Akira S, Azuma I, Hayashi A, Toyoshima K, Seya T | display-authors = 6 | title = Maturation of human dendritic cells by cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guérin: involvement of toll-like receptors | journal = Infection and Immunity | volume = 68 | issue = 12 | pages = 6883–6890 | date = December 2000 | pmid = 11083809 | pmc = 97794 | doi = 10.1128/IAI.68.12.6883-6890.2000 | editor-first = S. H. E. | editor-last = Kaufmann }}</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 | vauthors = Ryoma Y, Moriya Y, Okamoto M, Kanaya I, Saito M, Sato M | title = Biological effect of OK-432 (picibanil) and possible application to dendritic cell therapy | journal = Anticancer Research | volume = 24 | issue = 5C | pages = 3295–3301 | date = 2004-09-01 | pmid = 15515424 | url = https://ar.iiarjournals.org/content/24/5C/3295 }}</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 name="Okamoto_2004">{{cite journal | vauthors = Okamoto M, Oshikawa T, Tano T, Ohe G, Furuichi S, Nishikawa H, Ahmed SU, Akashi S, Miyake K, Takeuchi O, Akira S, Moriya Y, Matsubara S, Ryoma Y, Saito M, Sato M | title = Involvement of Toll-like receptor 4 signaling in interferon-gamma production and antitumor effect by streptococcal agent OK-432 | journal = Journal of the National Cancer Institute | volume = 95 | issue = 4 | pages = 316–26 | date = February 2003 | pmid = 12591988 | doi = 10.1093/jnci/95.4.316 | url = }}</ref>
-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 |last1=Berendt |first1=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 |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 |last1=Engelhardt |first1=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>.
+Purified LPS also showed potent anti-tumor efficacy as systemic therapeutic agents in several tumor models.<ref>{{cite journal | vauthors = Shear MB, Perrault M |title=Chemical Treatment of Tumors. IX. Reactions of Mice with Primary Subcutaneous Tumors to Injection of a Hemorrhage-Producing Bacterial Polysaccharide1 |journal=JNCI: Journal of the National Cancer Institute |date=April 1944 |volume=Journal of the National Cancer Institute | volume = 4 | issue =  5 | date =  April 1944,| pages = 461–476 |doi=10.1093/jnci/4.5.461}}</ref> <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 | vauthors = Berendt MJ, North RJ, Kirstein DP | title = The immunological basis of endotoxin-induced tumor regression. Requirement for a pre-existing state of concomitant anti-tumor immunity | journal = The Journal of Experimental Medicine | volume = 148 | issue = 6 | pages = 1560–1569 | date = December 1978 | pmid = 309922 | pmc = 2185097 | doi = 10.1084/jem.148.6.1560 }}</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 | vauthors = Engelhardt R, Mackensen A, Galanos C | title = Phase I trial of intravenously administered endotoxin (Salmonella abortus equi) in cancer patients | journal = Cancer Research | volume = 51 | issue = 10 | pages = 2524–2530 | date = May 1991 | pmid = 2021932 | url = https://pubmed.ncbi.nlm.nih.gov/2021932/ }}</ref>.
-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 |last1=Bhatia |first1=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 |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 |last1=Halwani |first1=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=April 2022 |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|s2cid=244943266 }}</ref><ref>{{Cite journal |last1=Flowers |first1=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 |doi-broken-date=2024-02-20 |issn=0006-4971}}</ref>.
+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 | vauthors = 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 | display-authors = 6 | title = Intratumoral G100, a TLR4 Agonist, Induces Antitumor Immune Responses and Tumor Regression in Patients with Merkel Cell Carcinoma | journal = Clinical Cancer Research | volume = 25 | issue = 4 | pages = 1185–1195 | date = February 2019 | pmid = 30093453 | pmc = 6368904 | doi = 10.1158/1078-0432.CCR-18-0469 }}</ref>, and potent adjuvant activity in phase 2 trials in combination with pembrolizumab in patients with follicular lymphoma <ref>{{cite journal | vauthors = 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, Chau I, von Keudell GR, Lu H, Yakovich A, Chen M, Meulen Jh T, Yurasov S, Hsu FJ, Flowers CR | display-authors = 6 | title = Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma | journal = Leukemia & Lymphoma | volume = 63 | issue = 4 | pages = 821–833 | date = April 2022 | pmid = 34865586 | doi = 10.1080/10428194.2021.2010057 | s2cid = 244943266 }}</ref><ref>{{Cite journal |last1=Flowers |first1=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 |doi-broken-date=2024-02-20 |issn=0006-4971}}</ref>.
-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 |last1=Rajput |first1=Sandeep |last2=Volk-Draper |first2=Lisa D. |last3=Ran |first3=Sophia |date=August 2013 |title=TLR4 is a novel determinant of the response to paclitaxel in breast cancer |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 |last1=Flowers |first1=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 |doi-broken-date=2024-02-20 |issn=0006-4971}}</ref>.
+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 | vauthors = Rajput S, Volk-Draper LD, Ran S | title = TLR4 is a novel determinant of the response to paclitaxel in breast cancer | journal = Molecular Cancer Therapeutics | volume = 12 | issue = 8 | pages = 1676–1687 | date = August 2013 | pmid = 23720768 | pmc = 3742631 | doi = 10.1158/1535-7163.MCT-12-1019 }}</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 |last1=Flowers |first1=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 |doi-broken-date=2024-02-20 |issn=0006-4971}}</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 |last1=Zhang |first1=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=October 2017 |title=Andrographolide suppresses proliferation of human colon cancer SW620 cells through the TLR4/NF-κB/MMP-9 signaling pathway |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 |last1=Wang |first1=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|s2cid=24926622 }}</ref><ref>{{Cite journal |last1=Kelly |first1=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 |last1=Jang |first1=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=December 2020 |title=Interactions between tumor-derived proteins and Toll-like receptors |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 |last1=Khademalhosseini |first1=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 |pmid=30543015 |s2cid=56143069 |issn=1880-4233}}</ref><ref>{{Cite journal |last1=Roh |first1=Jong Seong |last2=Sohn |first2=Dong Hyun |date=August 2018 |title=Damage-Associated Molecular Patterns in Inflammatory Diseases |journal=Immune Network |volume=18 |issue=4 |pages=e27 |doi=10.4110/in.2018.18.e27 |issn=1598-2629 |pmc=6117512 |pmid=30181915}}</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 | vauthors = Zhang R, Zhao J, Xu J, Jiao DX, Wang J, Gong ZQ, Jia JH | title = Andrographolide suppresses proliferation of human colon cancer SW620 cells through the TLR4/NF-κB/MMP-9 signaling pathway | journal = Oncology Letters | volume = 14 | issue = 4 | pages = 4305–4310 | date = October 2017 | pmid = 28943944 | pmc = 5604146 | doi = 10.3892/ol.2017.6669 }}</ref><ref>{{cite journal | vauthors = 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, Yuan SS | display-authors = 6 | title = Resistin facilitates breast cancer progression via TLR4-mediated induction of mesenchymal phenotypes and stemness properties | journal = Oncogene | volume = 37 | issue = 5 | pages = 589–600 | date = February 2018 | pmid = 28991224 | doi = 10.1038/onc.2017.357 | s2cid = 24926622 }}</ref><ref>{{cite journal | vauthors = Kelly MG, Alvero AB, Chen R, Silasi DA, Abrahams VM, Chan S, Visintin I, Rutherford T, Mor G | display-authors = 6 | title = TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer | journal = Cancer Research | volume = 66 | issue = 7 | pages = 3859–3868 | date = April 2006 | pmid = 16585214 | doi = 10.1158/0008-5472.CAN-05-3948 }}</ref>. Several studies showed that this is mediated by the misuse of DAMP signaling by tumor cells <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><ref>{{cite journal | vauthors = Khademalhosseini M, Arababadi MK | title = Toll-like receptor 4 and breast cancer: an updated systematic review | journal = Breast Cancer | volume = 26 | issue = 3 | pages = 265–271 | date = May 2019 | pmid = 30543015 | doi = 10.1007/s12282-018-00935-2 | s2cid = 56143069 }}</ref><ref>{{cite journal | vauthors = Roh JS, Sohn DH | title = Damage-Associated Molecular Patterns in Inflammatory Diseases | journal = Immune Network | volume = 18 | issue = 4 | pages = e27 | date = August 2018 | pmid = 30181915 | pmc = 6117512 | doi = 10.4110/in.2018.18.e27 }}</ref>.
-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 |last1=Jang |first1=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=December 2020 |title=Interactions between tumor-derived proteins and Toll-like receptors |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 |last1=Hernandez |first1=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 |journal=Oncogene |volume=35 |issue=46 |pages=5931–5941 |doi=10.1038/onc.2016.104 |issn=1476-5594 |pmc=5119456 |pmid=27086930}}</ref>.
+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 | 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>. 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 | 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>.
-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 |last1=Zhu |first1=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 |journal=PLOS ONE |volume=8 |issue=12 |pages=e82858 |doi=10.1371/journal.pone.0082858 |doi-access=free |issn=1932-6203 |pmc=3869723 |pmid=24376595|bibcode=2013PLoSO...882858Z }}</ref>.
+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 | vauthors = Zhu L, Yuan H, Jiang T, Wang R, Ma H, Zhang S | title = Association of TLR2 and TLR4 polymorphisms with risk of cancer: a meta-analysis | journal = PloS One | volume = 8 | issue = 12 | pages = e82858 | date = 2013-12-20 | pmid = 24376595 | pmc = 3869723 | doi = 10.1371/journal.pone.0082858 | doi-access = free | bibcode = 2013PLoSO...882858Z }}</ref>.
 === '''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 <ref>{{Cite journal |last1=Vaure |first1=Céline |last2=Liu |first2=Yuanqing |date=2014 |title=A Comparative Review of Toll-Like Receptor 4 Expression and Functionality in Different Animal Species |journal=Frontiers in Immunology |volume=5 |page=316 |doi=10.3389/fimmu.2014.00316 |doi-access=free |pmid=25071777 |pmc=4090903 |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 |last1=Wardill |first1=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=February 2015 |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 |last1=Molteni |first1=Monica |last2=Gemma |first2=Sabrina |last3=Rossetti |first3=Carlo |date=2016 |title=The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation |journal=Mediators of Inflammation |volume=2016 |pages=6978936 |doi=10.1155/2016/6978936 |doi-access=free |issn=1466-1861 |pmc=4887650 |pmid=27293318}}</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 | 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>. 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 | vauthors = Wardill HR, Van Sebille YZ, Mander KA, Gibson RJ, Logan RM, Bowen JM, Sonis ST | title = Toll-like receptor 4 signaling: a common biological mechanism of regimen-related toxicities: an emerging hypothesis for neuropathy and gastrointestinal toxicity | journal = Cancer Treatment Reviews | volume = 41 | issue = 2 | pages = 122–128 | date = February 2015 | pmid = 25512119 | doi = 10.1016/j.ctrv.2014.11.005 }}</ref><ref>{{cite journal | vauthors = Molteni M, Gemma S, Rossetti C | title = The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation | journal = Mediators of Inflammation | volume = 2016 | pages = 6978936 | date = 2016 | pmid = 27293318 | pmc = 4887650 | doi = 10.1155/2016/6978936 | doi-access = free }}</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 |last1=Tahara |first1=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=November 2006 |title=Role of toll-like receptor signalling in Abeta uptake and clearance |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>.
+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 | vauthors = Tahara K, Kim HD, Jin JJ, Maxwell JA, Li L, Fukuchi K | title = Role of toll-like receptor signalling in Abeta uptake and clearance | journal = Brain | volume = 129 | issue = Pt 11 | pages = 3006–3019 | date = November 2006 | pmid = 16984903 | pmc = 2445613 | doi = 10.1093/brain/awl249 }}</ref>.
-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 |last1=Buchanan |first1=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 |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 |last1=Qin |first1=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 |last1=Gambuzza |first1=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|s2cid=3277551 }}</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 |last1=Buchanan |first1=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 |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 |last1=Rannikko |first1=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 |journal=BMC Neuroscience |volume=16 |pages=57 |doi=10.1186/s12868-015-0192-0 |doi-access=free |issn=1471-2202 |pmc=4562100 |pmid=26346361}}</ref><ref>{{Cite journal |last1=Walter |first1=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|s2cid=6752610 }}</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=February 2015 |title=The Role of Damage-Associated Molecular Patterns in Human Diseases: Part I - Promoting inflammation and immunity |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 |last1=Festoff |first1=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 |journal=Journal of Neuroinflammation |volume=13 |issue=1 |pages=194 |doi=10.1186/s12974-016-0670-z |doi-access=free |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 |last1=Chaves |first1=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 |journal=Journal of Neuroinflammation |volume=7 |pages=6 |doi=10.1186/1742-2094-7-6 |doi-access=free |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 |last1=Yang |first1=Yi |last2=Han |first2=Chenyang |last3=Guo |first3=Li |last4=Guan |first4=Qiaobin |date=April 2018 |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 |journal=Brain and Behavior |volume=8 |issue=4 |pages=e00948 |doi=10.1002/brb3.948 |issn=2162-3279 |pmc=5893335 |pmid=29670828}}</ref>.
+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 | vauthors = Buchanan MM, Hutchinson M, Watkins LR, Yin H | title = Toll-like receptor 4 in CNS pathologies | journal = Journal of Neurochemistry | volume = 114 | issue = 1 | pages = 13–27 | date = July 2010 | pmid = 20402965 | pmc = 2909662 | doi = 10.1111/j.1471-4159.2010.06736.x }}</ref><ref>{{cite journal | vauthors = Qin Y, Liu Y, Hao W, Decker Y, Tomic I, Menger MD, Liu C, Fassbender K | display-authors = 6 | title = Stimulation of TLR4 Attenuates Alzheimer's Disease-Related Symptoms and Pathology in Tau-Transgenic Mice | journal = Journal of Immunology | volume = 197 | issue = 8 | pages = 3281–3292 | date = October 2016 | pmid = 27605009 | doi = 10.4049/jimmunol.1600873 }}</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 | vauthors = Gambuzza M, Licata N, Palella E, Celi D, Foti Cuzzola V, Italiano D, Marino S, Bramanti P | display-authors = 6 | title = Targeting Toll-like receptors: emerging therapeutics for multiple sclerosis management | journal = Journal of Neuroimmunology | volume = 239 | issue = 1-2 | pages = 1–12 | date = October 2011 | pmid = 21889214 | doi = 10.1016/j.jneuroim.2011.08.010 | s2cid = 3277551 }}</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 | vauthors = Buchanan MM, Hutchinson M, Watkins LR, Yin H | title = Toll-like receptor 4 in CNS pathologies | journal = Journal of Neurochemistry | volume = 114 | issue = 1 | pages = 13–27 | date = July 2010 | pmid = 20402965 | pmc = 2909662 | doi = 10.1111/j.1471-4159.2010.06736.x }}</ref><ref>{{cite journal | vauthors = Rannikko EH, Weber SS, Kahle PJ | title = Exogenous α-synuclein induces toll-like receptor 4 dependent inflammatory responses in astrocytes | journal = BMC Neuroscience | volume = 16 | pages = 57 | date = September 2015 | pmid = 26346361 | pmc = 4562100 | doi = 10.1186/s12868-015-0192-0 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, Bode B, Manietta N, Walter J, Schulz-Schuffer W, Fassbender K | display-authors = 6 | title = Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease | journal = Cellular Physiology and Biochemistry | volume = 20 | issue = 6 | pages = 947–956 | date = 2007 | pmid = 17982277 | doi = 10.1159/000110455 | s2cid = 6752610 }}</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 | vauthors = Land WG | title = The Role of Damage-Associated Molecular Patterns in Human Diseases: Part I - Promoting inflammation and immunity | journal = Sultan Qaboos University Medical Journal | volume = 15 | issue = 1 | pages = e9-e21 | date = February 2015 | pmid = 25685392 | pmc = 4318613 }}</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 | vauthors = Festoff BW, Sajja RK, van Dreden P, Cucullo L | title = HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer's disease | journal = Journal of Neuroinflammation | volume = 13 | issue = 1 | pages = 194 | date = August 2016 | pmid = 27553758 | pmc = 4995775 | doi = 10.1186/s12974-016-0670-z | doi-access = free }}</ref>. In AD patients, the serum levels of S100B are also intimately related to the severity of the disease <ref>{{cite journal | vauthors = Chaves ML, Camozzato AL, Ferreira ED, Piazenski I, Kochhann R, Dall'Igna O, Mazzini GS, Souza DO, Portela LV | display-authors = 6 | title = Serum levels of S100B and NSE proteins in Alzheimer's disease patients | journal = Journal of Neuroinflammation | volume = 7 | pages = 6 | date = January 2010 | pmid = 20105309 | pmc = 2832635 | doi = 10.1186/1742-2094-7-6 | doi-access = free }}</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 | vauthors = Yang Y, Han C, Guo L, Guan Q | 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 | journal = Brain and Behavior | volume = 8 | issue = 4 | pages = e00948 | date = April 2018 | pmid = 29670828 | pmc = 5893335 | doi = 10.1002/brb3.948 }}</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 |last1=Wu |first1=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 |journal=Mediators of Inflammation |language=en |volume=2022 |pages=1–20 |doi=10.1155/2022/7924199 |doi-access=free |pmid=36046763 |pmc=9420645 |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 |last1=Leitner |first1=Gunnar R. |last2=Wenzel |first2=Tyler J. |last3=Marshall |first3=Nick |last4=Gates |first4=Ellen J. |last5=Klegeris |first5=Andis |date=October 2019 |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|s2cid=203652175 }}</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 |last1=Michaud |first1=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 |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 |doi-access=free |issn=1091-6490 |pmc=3562771 |pmid=23322736|bibcode=2013PNAS..110.1941M }}</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 |last1=Leitner |first1=Gunnar R. |last2=Wenzel |first2=Tyler J. |last3=Marshall |first3=Nick |last4=Gates |first4=Ellen J. |last5=Klegeris |first5=Andis |date=October 2019 |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|s2cid=203652175 }}</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 | vauthors = Wu L, Xian X, Xu G, Tan Z, Dong F, Zhang M, Zhang F | title = Toll-Like Receptor 4: A Promising Therapeutic Target for Alzheimer's Disease | journal = Mediators of Inflammation | volume = 2022 | pages = 7924199 | date = 2022-08-21 | pmid = 36046763 | pmc = 9420645 | doi = 10.1155/2022/7924199 | doi-access = free }}</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 | vauthors = Leitner GR, Wenzel TJ, Marshall N, Gates EJ, Klegeris A | title = Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders | journal = Expert Opinion on Therapeutic Targets | volume = 23 | issue = 10 | pages = 865–882 | date = October 2019 | pmid = 31580163 | doi = 10.1080/14728222.2019.1676416 | s2cid = 203652175 }}</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 | vauthors = 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 | display-authors = 6 | title = Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer's disease-related pathology | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 5 | pages = 1941–1946 | date = January 2013 | pmid = 23322736 | pmc = 3562771 | doi = 10.1073/pnas.1215165110 | doi-access = free | bibcode = 2013PNAS..110.1941M }}</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 | vauthors = Leitner GR, Wenzel TJ, Marshall N, Gates EJ, Klegeris A | title = Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders | journal = Expert Opinion on Therapeutic Targets | volume = 23 | issue = 10 | pages = 865–882 | date = October 2019 | pmid = 31580163 | doi = 10.1080/14728222.2019.1676416 | s2cid = 203652175 }}</ref>.
 == Drugs targeting TLR4 ==
-TLR4 has been shown to be important for the long-term side-effects of [[opioid]] [[analgesic]] drugs. Various [[Mu opioid receptor|μ-opioid]] [[Receptor (biochemistry)|receptor]] ligands have been tested and found to also possess action as agonists or antagonists of TLR4, with opioid agonists such as [[(%2B)-Morphine|(+)-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 [[Tumor necrosis factor-alpha|TNF-α]] and [[IL1B|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 [[Drug tolerance|tolerance]] to opioid analgesic drugs,<ref name="pmid15836969">{{cite journal | vauthors = Shavit Y, Wolf G, Goshen I, Livshits D, Yirmiya R | title = Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance | journal = Pain | volume = 115 | issue = 1–2 | pages = 50–59 | date = May 2005 | pmid = 15836969 | doi = 10.1016/j.pain.2005.02.003 | s2cid = 7286123 }}</ref><ref name="pmid20615556">{{cite journal | vauthors = Mohan S, Davis RL, DeSilva U, Stevens CW | title = Dual regulation of mu opioid receptors in SK-N-SH neuroblastoma cells by morphine and interleukin-1β: evidence for opioid-immune crosstalk | journal = Journal of Neuroimmunology | volume = 227 | issue = 1–2 | pages = 26–34 | date = October 2010 | pmid = 20615556 | pmc = 2942958 | doi = 10.1016/j.jneuroim.2010.06.007 }}</ref> and in the emergence of side-effects such as [[hyperalgesia]] and [[allodynia]] that can become a problem following extended use of opioid drugs.<ref name="pmid19607972">{{cite book | vauthors = Komatsu T, Sakurada S, Katsuyama S, Sanai K, Sakurada T | title = Mechanism of allodynia evoked by intrathecal morphine-3-glucuronide in mice | volume = 85 | pages = 207–19 | year = 2009 | pmid = 19607972 | doi = 10.1016/S0074-7742(09)85016-2 | isbn = 978-0-12-374893-5 | series = International Review of Neurobiology }}</ref><ref name="pmid19833175">{{cite journal | vauthors = Lewis SS, Hutchinson MR, Rezvani N, Loram LC, Zhang Y, Maier SF, Rice KC, Watkins LR | display-authors = 6 | title = Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta | journal = Neuroscience | volume = 165 | issue = 2 | pages = 569–583 | date = January 2010 | pmid = 19833175 | pmc = 2795035 | doi = 10.1016/j.neuroscience.2009.10.011 }}</ref> 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,<ref name="pmid21081778">{{cite journal | vauthors = Shen CH, Tsai RY, Shih MS, Lin SL, Tai YH, Chien CC, Wong CS | title = Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats | journal = Anesthesia and Analgesia | volume = 112 | issue = 2 | pages = 454–459 | date = February 2011 | pmid = 21081778 | doi = 10.1213/ANE.0b013e3182025b15 | s2cid = 12295407 | doi-access = free }}</ref><ref name="pmid20974246">{{cite journal | vauthors = Hook MA, Washburn SN, Moreno G, Woller SA, Puga D, Lee KH, Grau JW | title = An IL-1 receptor antagonist blocks a morphine-induced attenuation of locomotor recovery after spinal cord injury | journal = Brain, Behavior, and Immunity | volume = 25 | issue = 2 | pages = 349–359 | date = February 2011 | pmid = 20974246 | pmc = 3025088 | doi = 10.1016/j.bbi.2010.10.018 }}</ref> and this has also been demonstrated with drugs that block TLR4 itself.
+TLR4 has been shown to be important for the long-term side-effects of [[opioid]] [[analgesic]] drugs. Various [[Mu opioid receptor|μ-opioid]] [[Receptor (biochemistry)|receptor]] ligands have been tested and found to also possess action as agonists or antagonists of TLR4, with opioid agonists such as [[(%2B)-Morphine|(+)-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 [[Tumor necrosis factor-alpha|TNF-α]] and [[IL1B|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 [[Drug tolerance|tolerance]] to opioid analgesic drugs,<ref name="pmid15836969">{{cite journal | vauthors = Shavit Y, Wolf G, Goshen I, Livshits D, Yirmiya R | title = Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance | journal = Pain | volume = 115 | issue = 1-2 | pages = 50–59 | date = May 2005 | pmid = 15836969 | doi = 10.1016/j.pain.2005.02.003 | s2cid = 7286123 }}</ref><ref name="pmid20615556">{{cite journal | vauthors = Mohan S, Davis RL, DeSilva U, Stevens CW | title = Dual regulation of mu opioid receptors in SK-N-SH neuroblastoma cells by morphine and interleukin-1β: evidence for opioid-immune crosstalk | journal = Journal of Neuroimmunology | volume = 227 | issue = 1-2 | pages = 26–34 | date = October 2010 | pmid = 20615556 | pmc = 2942958 | doi = 10.1016/j.jneuroim.2010.06.007 }}</ref> and in the emergence of side-effects such as [[hyperalgesia]] and [[allodynia]] that can become a problem following extended use of opioid drugs.<ref name="pmid19607972">{{cite book | vauthors = Komatsu T, Sakurada S, Katsuyama S, Sanai K, Sakurada T | title = Mechanism of allodynia evoked by intrathecal morphine-3-glucuronide in mice | volume = 85 | pages = 207–19 | year = 2009 | pmid = 19607972 | doi = 10.1016/S0074-7742(09)85016-2 | isbn = 978-0-12-374893-5 | series = International Review of Neurobiology }}</ref><ref name="pmid19833175">{{cite journal | vauthors = Lewis SS, Hutchinson MR, Rezvani N, Loram LC, Zhang Y, Maier SF, Rice KC, Watkins LR | display-authors = 6 | title = Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta | journal = Neuroscience | volume = 165 | issue = 2 | pages = 569–583 | date = January 2010 | pmid = 19833175 | pmc = 2795035 | doi = 10.1016/j.neuroscience.2009.10.011 }}</ref> 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,<ref name="pmid21081778">{{cite journal | vauthors = Shen CH, Tsai RY, Shih MS, Lin SL, Tai YH, Chien CC, Wong CS | title = Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats | journal = Anesthesia and Analgesia | volume = 112 | issue = 2 | pages = 454–459 | date = February 2011 | pmid = 21081778 | doi = 10.1213/ANE.0b013e3182025b15 | s2cid = 12295407 | doi-access = free }}</ref><ref name="pmid20974246">{{cite journal | vauthors = Hook MA, Washburn SN, Moreno G, Woller SA, Puga D, Lee KH, Grau JW | title = An IL-1 receptor antagonist blocks a morphine-induced attenuation of locomotor recovery after spinal cord injury | journal = Brain, Behavior, and Immunity | volume = 25 | issue = 2 | pages = 349–359 | date = February 2011 | pmid = 20974246 | pmc = 3025088 | doi = 10.1016/j.bbi.2010.10.018 }}</ref> 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.<ref name="pmid19762094">{{cite journal | vauthors = Watkins LR, Hutchinson MR, Rice KC, Maier SF | title = The "toll" of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia | journal = Trends in Pharmacological Sciences | volume = 30 | issue = 11 | pages = 581–591 | date = November 2009 | pmid = 19762094 | pmc = 2783351 | doi = 10.1016/j.tips.2009.08.002 }}</ref><ref name="pmid18662331">{{cite journal | vauthors = Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, Patel SJ, Crysdale NY, Harrison JA, Maier SF, Rice KC, Watkins LR | display-authors = 6 | title = Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4) | journal = The European Journal of Neuroscience | volume = 28 | issue = 1 | pages = 20–29 | date = July 2008 | pmid = 18662331 | pmc = 2588470 | doi = 10.1111/j.1460-9568.2008.06321.x }}</ref> 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.<ref name="pmid18599265">{{cite journal | vauthors = Hutchinson MR, Coats BD, Lewis SS, Zhang Y, Sprunger DB, Rezvani N, Baker EM, Jekich BM, Wieseler JL, Somogyi AA, Martin D, Poole S, Judd CM, Maier SF, Watkins LR | display-authors = 6 | title = Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia | journal = Brain, Behavior, and Immunity | volume = 22 | issue = 8 | pages = 1178–1189 | date = November 2008 | pmid = 18599265 | pmc = 2783238 | doi = 10.1016/j.bbi.2008.05.004 }}</ref><ref name="pmid18662331" /><ref name="pmid20178837">{{cite journal | vauthors = Hutchinson MR, Lewis SS, Coats BD, Rezvani N, Zhang Y, Wieseler JL, Somogyi AA, Yin H, Maier SF, Rice KC, Watkins LR | display-authors = 6 | title = Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences | journal = Neuroscience | volume = 167 | issue = 3 | pages = 880–893 | date = May 2010 | pmid = 20178837 | pmc = 2854318 | doi = 10.1016/j.neuroscience.2010.02.011 }}</ref> This may also be the mechanism behind the beneficial effect of ultra-low dose naltrexone on opioid analgesia.<ref name="pmid19799935">{{cite journal | vauthors = Lin SL, Tsai RY, Tai YH, Cherng CH, Wu CT, Yeh CC, Wong CS | title = Ultra-low dose naloxone upregulates interleukin-10 expression and suppresses neuroinflammation in morphine-tolerant rat spinal cords | journal = Behavioural Brain Research | volume = 207 | issue = 1 | pages = 30–36 | date = February 2010 | pmid = 19799935 | doi = 10.1016/j.bbr.2009.09.034 | s2cid = 5128970 }}</ref>
@@ Line 90: / 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 |last1=Yang |first1=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=4291531 |pmid=25559892}}</ref><ref>{{Cite journal |last1=Manček-Keber |first1=Mateja |last2=Jerala |first2=Roman |date=February 2015 |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 |pmid=25476977 |s2cid=32029412 |issn=0014-2980}}</ref><ref>{{Cite journal |last1=Kim |first1=Ho Min |last2=Kim |first2=You-Me |date=October 2018 |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|pmid=30332623 }}</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>{{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 = 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 | s2cid = 32029412 }}</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 }}</ref>.
 === Antagonists ===
-As of 2020, there were no specific TLR4 antagonists approved as drugs.<ref>{{cite journal | vauthors = Romerio A, Peri F | title = Increasing the Chemical Variety of Small-Molecule-Based TLR4 Modulators: An Overview | journal = Frontiers in Immunology | volume = 11 | page = 1210 | date = 2020 | pmid = 32765484 | pmc = 7381287 | doi = 10.3389/fimmu.2020.01210 | doi-access = free }}</ref>
+As of 2020, there were no specific TLR4 antagonists approved as drugs.<ref>{{cite journal | vauthors = Romerio A, Peri F | title = Increasing the Chemical Variety of Small-Molecule-Based TLR4 Modulators: An Overview | journal = Frontiers in Immunology | volume = 11 | pages = 1210 | date = 2020 | pmid = 32765484 | pmc = 7381287 | doi = 10.3389/fimmu.2020.01210 | doi-access = free }}</ref>
 {{div col|colwidth=20em}}
 * [[Amitriptyline]]<ref name="pmid20381591">{{cite journal | vauthors = Hutchinson MR, Loram LC, Zhang Y, Shridhar M, Rezvani N, Berkelhammer D, Phipps S, Foster PS, Landgraf K, Falke JJ, Rice KC, Maier SF, Yin H, Watkins LR | display-authors = 6 | title = Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity | journal = Neuroscience | volume = 168 | issue = 2 | pages = 551–563 | date = June 2010 | pmid = 20381591 | pmc = 2872682 | doi = 10.1016/j.neuroscience.2010.03.067 }}</ref>
@@ Line 103: / Line 103: @@
 * [[Ibudilast]]<ref name="pmid22776604">{{cite journal | vauthors = Jia ZJ, Wu FX, Huang QH, Liu JM | title = [Toll-like receptor 4: the potential therapeutic target for neuropathic pain] | journal = Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae | volume = 34 | issue = 2 | pages = 168–173 | date = April 2012 | pmid = 22776604 | doi = 10.3881/j.issn.1000-503X.2012.02.013 }}</ref>
 * [[Pinocembrin]]<ref name="pmid28007523">{{cite journal | vauthors = Lan X, Han X, Li Q, Li Q, Gao Y, Cheng T, Wan J, Zhu W, Wang J | display-authors = 6 | title = Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia | journal = Brain, Behavior, and Immunity | volume = 61 | pages = 326–339 | date = March 2017 | pmid = 28007523 | pmc = 5453178 | doi = 10.1016/j.bbi.2016.12.012 }}</ref>
-* [[Resatorvid]]<ref name="pmid31697454">{{cite journal | vauthors = Kaieda A, Takahashi M, Fukuda H, Okamoto R, Morimoto S, Gotoh M, Miyazaki T, Hori Y, Unno S, Kawamoto T, Tanaka T, Itono S, Takagi T, Sugimoto H, Okada K, Lane W, Sang BC, Saikatendu K, Matsunaga S, Miwatashi S | display-authors = 6 | title = Structure-Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]Pyridin-2-one-Based p38 MAP Kinase Inhibitors: Part 2 | journal = ChemMedChem | volume = 14 | issue = 24 | pages = 2093–2101 | date = December 2019 | pmid = 31697454 | doi = 10.1002/cmdc.201900373 | s2cid = 207951964 }}</ref>
+* [[Resatorvid]]<ref name="pmid31697454">{{cite journal | vauthors = Kaieda A, Takahashi M, Fukuda H, Okamoto R, Morimoto S, Gotoh M, Miyazaki T, Hori Y, Unno S, Kawamoto T, Tanaka T, Itono S, Takagi T, Sugimoto H, Okada K, Lane W, Sang BC, Saikatendu K, Matsunaga S, Miwatashi S | display-authors = 6 | title = Structure-Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]Pyridin-2-one-Based p38 MAP Kinase Inhibitors: Part 2 | journal = ChemMedChem | volume = 14 | issue = 24 | pages = 2093–2101 | date = December 2019 | pmid = 31697454 | doi = 10.1002/cmdc.201900373 | s2cid = 207951964 }}</ref>
 * [[M62812]]
 * [[Naloxone]]<ref name="pmid19679181">{{cite journal | vauthors = Hutchinson MR, Zhang Y, Shridhar M, Evans JH, Buchanan MM, Zhao TX, Slivka PF, Coats BD, Rezvani N, Wieseler J, Hughes TS, Landgraf KE, Chan S, Fong S, Phipps S, Falke JJ, Leinwand LA, Maier SF, Yin H, Rice KC, Watkins LR | display-authors = 6 | title = Evidence that opioids may have toll-like receptor 4 and MD-2 effects | journal = Brain, Behavior, and Immunity | volume = 24 | issue = 1 | pages = 83–95 | date = January 2010 | pmid = 19679181 | pmc = 2788078 | doi = 10.1016/j.bbi.2009.08.004 }}</ref>
@@ Line 113: / Line 113: @@
 * [[Pentoxifylline]]<ref>{{cite journal | vauthors = Speer EM, Dowling DJ, Ozog LS, Xu J, Yang J, Kennady G, Levy O | title = Pentoxifylline inhibits TLR- and inflammasome-mediated in vitro inflammatory cytokine production in human blood with greater efficacy and potency in newborns | journal = Pediatric Research | volume = 81 | issue = 5 | pages = 806–816 | date = May 2017 | pmid = 28072760 | doi = 10.1038/pr.2017.6 | s2cid = 47210724 | doi-access = free }}</ref> (and downregulate TLR4 expression<ref>{{cite journal | vauthors = Schüller SS, Wisgrill L, Herndl E, Spittler A, Förster-Waldl E, Sadeghi K, Kramer BW, Berger A | display-authors = 6 | title = Pentoxifylline modulates LPS-induced hyperinflammation in monocytes of preterm infants in vitro | journal = Pediatric Research | volume = 82 | issue = 2 | pages = 215–225 | date = August 2017 | pmid = 28288151 | doi = 10.1038/pr.2017.41 | s2cid = 24897100 | doi-access = free }}</ref>)
 * [[Tapentadol]] (mixed agonist/antagonist)
-* [[TLR4-IN-C34]]<ref name="pmid23776545">{{cite journal | vauthors = Neal MD, Jia H, Eyer B, Good M, Guerriero CJ, Sodhi CP, Afrazi A, Prindle T, Ma C, Branca M, Ozolek J, Brodsky JL, Wipf P, Hackam DJ | display-authors = 6 | title = Discovery and validation of a new class of small molecule Toll-like receptor 4 (TLR4) inhibitors | journal = PLOS ONE | volume = 8 | issue = 6 | pages = e65779 | date = 2013 | pmid = 23776545 | pmc = 3680486 | doi = 10.1371/journal.pone.0065779 | doi-access = free | bibcode = 2013PLoSO...865779N }}</ref>
+* [[TLR4-IN-C34]]<ref name="pmid23776545">{{cite journal | vauthors = Neal MD, Jia H, Eyer B, Good M, Guerriero CJ, Sodhi CP, Afrazi A, Prindle T, Ma C, Branca M, Ozolek J, Brodsky JL, Wipf P, Hackam DJ | display-authors = 6 | title = Discovery and validation of a new class of small molecule Toll-like receptor 4 (TLR4) inhibitors | journal = PloS One | volume = 8 | issue = 6 | pages = e65779 | date = 2013 | pmid = 23776545 | pmc = 3680486 | doi = 10.1371/journal.pone.0065779 | doi-access = free | bibcode = 2013PLoSO...865779N }}</ref>
 * [[Palmitoylethanolamide]]<ref>{{cite journal | vauthors = Impellizzeri D, Campolo M, Di Paola R, Bruschetta G, de Stefano D, Esposito E, Cuzzocrea S |doi =  10.1177/1721727X15575869|title = Ultramicronized palmitoylethanolamide reduces inflammation an a Th1-mediated model of colitis|journal = European Journal of Inflammation|volume = 13|pages = 14–31|year = 2015 |s2cid = 79398556|doi-access = free}}</ref>
 {{Div col end}}

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