Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, though the latter two are not found in humans.
- 1 Function
- 2 Superfamily
- 3 Extended family
- 4 Summary of known mammalian TLRs
- 5 Ligands
- 6 Signaling
- 7 Medical relevance
- 8 Discovery
- 9 Notes and references
- 10 See also
- 11 External links
The ability of immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of Immune receptors called toll-like receptors (TLRs) that are expressed on the membranes of leukocytes including dendritic cells, macrophages, natural killer cells, cells of the adaptive immunity (T and B lymphocytes) and non immune cells (epithelial and endothelial cells, and fibroblasts).
The binding of ligands - either in the form of adjuvant used in vaccinations or in the form of invasive moieties during times of natural infection - to the TLR marks the key molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity.
Upon activation, TLRs recruit adapter proteins[disambiguation needed] (proteins that mediate other protein-protein interactions) within the cytosol of the immune cell in order to propagate the antigen-induced signal transduction pathway. These recruited proteins are then responsible for the subsequent activation of other downstream proteins, including protein kinases (IKKi, IRAK1, IRAK4, and TBK1) that further amplify the signal and ultimately lead to the upregulation or suppression of genes that orchestrate inflammatory responses and other transcriptional events. Some of these events lead to cytokine production, proliferation, and survival, while others lead to greater adaptive immunity. If the ligand is a bacterial factor, the pathogen might be phagocytosed and digested, and its antigens presented to CD4+ T cells. In the case of a viral factor, the infected cell may shut off its protein synthesis and may undergo programmed cell death (apoptosis). Immune cells that have detected a virus may also release anti-viral factors such as interferons.
Toll-like receptors have also been shown to be an important link between innate and adaptive immunity through their presence in dendritic cells. Flagellin, a TLR5 ligand induces cytokine secretion on interacting with TLR5 on human T cells.
TLRs are a type of pattern recognition receptor (PRR) and recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). TLRs together with the Interleukin-1 receptors form a receptor superfamily, known as the "interleukin-1 receptor / toll-like receptor superfamily"; all members of this family have in common a so-called TIR (toll-IL-1 receptor) domain.
Three subgroups of TIR domains exist. Proteins with subgroup 1 TIR domains are receptors for interleukins that are produced by macrophages, monocytes, and dendritic cells and all have extracellular Immunoglobulin (Ig) domains. Proteins with subgroup 2 TIR domains are classical TLRs, and bind directly or indirectly to molecules of microbial origin. A third subgroup of proteins containing TIR domains consists of adaptor proteins that are exclusively cytosolic and mediate signaling from proteins of subgroups 1 and 2.
TLRs are present in vertebrates, as well as in invertebrates. Molecular building blocks of the TLRs are represented in bacteria and in plants, and plant pattern recognition receptors are well known to be required for host defence against infection. The TLRs thus appear to be one of the most ancient, conserved components of the immune system.
In recent years TLRs were identified also in the mammalian nervous system. Members of the TLR family were detected on glia, neurons and on neural progenitor cells in which they regulate cell-fate decision.
It has been estimated that most mammalian species have between ten and fifteen types of toll-like receptors. Thirteen TLRs (named simply TLR1 to TLR13) have been identified in humans and mice together, and equivalent forms of many of these have been found in other mammalian species. However, equivalents of certain TLR found in humans are not present in all mammals. For example, a gene coding for a protein analogous to TLR10 in humans is present in mice, but appears to have been damaged at some point in the past by a retrovirus. On the other hand, mice express TLRs 11, 12, and 13, none of which is represented in humans. Other mammals may express TLRs that are not found in humans. Other non-mammalian species may have TLRs distinct from mammals, as demonstrated by TLR14, which is found in the Takifugu pufferfish. This may complicate the process of using experimental animals as models of human innate immunity.
TLRs in Drosophila immunity
Drosophila melanogaster has only innate immune responses. Response to fungal or bacterial infection occurs through two distinct signalling cascades, one of which is toll pathway and the other is immune deficiency (IMD) pathway. The toll pathway is similar to mammalian TLR signalling, but unlike mammalian TLRs, toll is not activated directly by pathogen-associated molecular patterns (PAMPs). Its receptor ectodomain recognizes cleaved form of the cytokine Spätzle, which is secreted in the haemolymph as inactive dimeric precursor. Toll receptor shares the cytoplasmatic TIR domain with mammalian TLRs, but ectodomain and intracytoplasmatic tail are different. This difference might reflect a function of these receptors as cytokine receptors rather than PRRs. Toll pathway is activated by different stimuli, such as Gram positive bacteria, fungi and virulence factors. First, the Spätzle processing enzyme (SPE) is activated in response to infection and cleaves Spätzle. Cleaved Spätzle then binds to toll receptor and crosslinks its ectodomains. This triggers conformational changes in receptor resulting in signalling through toll. Signalling now is very similar to mammalian signalling through TLRs. Toll-induced signalling complex (TICS) is formed, comprising MyD88, Tube and Pelle (the orthologue of mammalian IRAK). Signal from TICS is then transduced to Cactus (homologue of mammalian IκB), phosphorylated Cactus is polyubiquitylated and degraded, allowing nuclear translocation of DIF (dorsal-related immunity facor; a homologue of mammalian NF-κB) and induction of transcription of genes for antimicrobial peptides (AMPs) such as Drosomycin.
TLR2 has also been designated as CD282 (cluster of differentiation 282).
TLR3 does not use the MyD88 dependent pathway. Its ligand is retroviral double-stranded RNA (dsRNA), which activates the TRIF dependent signalling pathway. To explore the role of this pathway in retroviral reprograming, knock down techniques of TLR3 or TRIF were prepared, and results showed that only the TLR3 pathway is required for full induction of target gene expression by the retrovirus expression vector. This retroviral expression of four transcriptional factors (Oct4, Sox2, Klf4 and c-Myc; OSKM) induces pluripotency in somatic cells. This is supported by study, which shows, that efﬁciency and amount of human iPSC generation, using retroviral vectors, is reduced by knockdown of the pathway with peptide inhibitors or shRNA knockdown of TLR3 or its adaptor protein TRIF. Taken together, stimulation of TLR3 causes great changes in chromatin remodeling and nuclear reprogramming, and activation of inflammatory pathways is required for these changes, induction of pluripotency genes and generation of human induced pluripotent stem cells (iPSC) colonies.
As noted above, human cells do not express TLR11, but mice cells do. Mouse-specific TLR11 recognizes uropathogenic E.coli and the apicomplexan parasite Toxoplasma gondii. With Toxoplasma its ligand is the protein profilin, but the ligand for E. coli is still not known. Recently the enteropathogen Salmonella spp. was found to have a ligand which is bound by TLR11. Salmonella is a gram-negative flagellated bacterium which causes food- and waterborne gastroenteritis and typhoid fever in humans. TLR11 in mouse intestine recognizes the flagellun protein flagellin, causing dimerization of the receptor, activation of NF-κB and production of inflammatory cytokines. TLR11 deficient mice (knockout mouse) are efficiently infected with orally administered Salmonella Typhi. S. Typhi does not normally infect mice, it is human obligatory pathogen that causes typhoid fever, which affects more than 20 million people and causes more than 220 thousand deaths per year. Because of this, studies were carried out and it was found that tlr-/- mice can be immunized against S. Typhi and they are used as an animal model for studying immune responses against this pathogen and for the development of vaccines, that could be possibly used in the future.
Summary of known mammalian TLRs
Toll-like receptors bind and become activated by different ligands, which, in turn, are located on different types of organisms or structures. They also have different adapters to respond to activation and are located sometimes at the cell surface and sometimes to internal cell compartments. Furthermore, they are expressed by different types of leucocytes or other cell types:
|Receptor||Ligand(s)||Ligand location||Adapter(s)||Location||Cell types|
|TLR 1||multiple triacyl lipopeptides||Bacterial lipoprotein||MyD88/MAL||cell surface|
|TLR 2||multiple glycolipids||Bacterial peptidoglycans||MyD88/MAL||cell surface|
|multiple lipopeptides||Bacterial peptidoglycans|
|multiple lipoproteins||Bacterial peptidoglycans|
|lipoteichoic acid||Gram-positive bacteria|
|TLR 3||double-stranded RNA, poly I:C||viruses||TRIF||cell compartment||
|TLR 4||lipopolysaccharide||Gram-negative bacteria||MyD88/MAL/TRIF/TRAM||cell surface|
|several heat shock proteins||Bacteria and host cells|
|heparan sulfate fragments||host cells|
|hyaluronic acid fragments||host cells|
|Various opioid drugs|
|TLR 5||Bacterial flagellin||Bacteria||MyD88||cell surface||
|TLR 6||multiple diacyl lipopeptides||Mycoplasma||MyD88/MAL||cell surface||
|TLR 7||imidazoquinoline||small synthetic compounds||MyD88||cell compartment|
|loxoribine (a guanosine analogue)|
|single-stranded RNA||RNA viruses|
|TLR 8||small synthetic compounds; single-stranded Viral RNA, phagocytized bacterial RNA(24)||MyD88||cell compartment|
|TLR 9||unmethylated CpG Oligodeoxynucleotide DNA||Bacteria, DNA viruses||MyD88||cell compartment||
|TLR 11||Profilin||Toxoplasma gondii||MyD88||cell compartment|
|TLR 12||Profilin||Toxoplasma gondii||MyD88||
|TLR 13||bacterial ribosomal RNA sequence "CGGAAAGACC"||Virus, bacteria||MyD88, TAK-1||cell compartment||
Because of the specificity of toll-like receptors (and other innate immune receptors) they cannot easily be changed in the course of evolution, these receptors recognize molecules that are constantly associated with threats (i.e., pathogen or cell stress) and are highly specific to these threats (i.e., cannot be mistaken for self molecules that are normally expressed under physiological conditions). Pathogen-associated molecules that meet this requirement are thought to be critical to the pathogen's function and difficult to change through mutation; they are said to be evolutionarily conserved. Somewhat conserved features in pathogens include bacterial cell-surface lipopolysaccharides (LPS), lipoproteins, lipopeptides, and lipoarabinomannan; proteins such as flagellin from bacterial flagella; double-stranded RNA of viruses; or the unmethylated CpG islands of bacterial and viral DNA; and also of the CpG islands found in the promoters of eukaryotic DNA; as well as certain other RNA and DNA molecules. For most of the TLRs, ligand recognition specificity has now been established by gene targeting (also known as "gene knockout"): a technique by which individual genes may be selectively deleted in mice. See the table below for a summary of known TLR ligands.
The stereotypic inflammatory response provoked by toll Like-Receptor activation has prompted speculation that endogenous activators of toll-like receptors might participate in autoimmune diseases. TLRs have been suspected of binding to host molecules including fibrinogen (involved in blood clotting), heat shock proteins (HSPs), HMGB1, extracellular matrix components and self DNA (it is normally degraded by nucleases, but under inflammatory and autoimmune conditions it can form a complex with endogenous proteins, become resistant to these nucleases and gain access to endosomal TLRs as TLR7 or TLR9). These endogenous ligands are usually produced as a result of non-physiological cell death.
Different TLRs can recognize different antigens as listed below.
TLR 1: bacterial lipoprotein and peptidoglycans
TLR 2: bacterial peptidoglycans
TLR 3: double-stranded RNA
TLR 4: lipopolysaccharides
TLR 5: bacterial flagella
TLR 6: bacterial lipoprotein
TLR 7: single-stranded RNA, bacterial and viral
TLR 9: CpG DNA
TLR 10: unknown
TLR 12: profilin from Toxoplasma gondii
TLRs are believed to function as dimers. Though most TLRs appear to function as homodimers, TLR2 forms heterodimers with TLR1 or TLR6, each dimer having a different ligand specificity. TLRs may also depend on other co-receptors for full ligand sensitivity, such as in the case of TLR4's recognition of LPS, which requires MD-2. CD14 and LPS-Binding Protein (LBP) are known to facilitate the presentation of LPS to MD-2.
A set of endosomal TLRs comprising TLR3, TLR7, TLR8 and TLR9 recognize nucleic acid derived from viruses as well as endogenous nucleic acids in context of pathogenic events. Activation of these receptor leads to production of inflammatory cytokines as well as type I interferons (interferon type I) to help fighting viral infection.
The adapter proteins and kinases that mediate TLR signaling have also been targeted. In addition, random germline mutagenesis with ENU has been used to decipher the TLR signaling pathways. When activated, TLRs recruit adapter molecules within the cytoplasm of cells in order to propagate a signal. Four adapter molecules are known to be involved in signaling. These proteins are known as MyD88, Tirap (also called Mal), Trif, and Tram (TRIF-related adaptor molecule).
TLR signaling is divided into two distinct signaling pathways, the MyD88-dependent and TRIF-dependent pathway.
The MyD88-dependent response occurs on dimerization of the TLR receptor, and is utilized by every TLR except TLR3. Its primary effect is activation of NFκB and Mitogen-activated protein kinase. Ligand binding and conformational change that occurs in the receptor recruits the adaptor protein MyD88, a member of the TIR family. MyD88 then recruits IRAK4, IRAK1 and IRAK2. IRAK kinases then phosphorylate and activate the protein TRAF6, which in turn polyubiquinates the protein TAK1, as well as itself in order to facilitate binding to IKK-β. On binding, TAK1 phosphorylates IKK-β, which then phosphorylates IκB causing its degradation and allowing NFκB to diffuse into the cell nucleus and activate transcription and consequent induction of inflammatory cytokines.
Both TLR3 and TLR4 utilize the TRIF-dependent pathway, which is triggered by dsRNA and LPS, respectively. For TLR3, dsRNA leads to activation of the receptor, recruiting the adaptor TRIF. TRIF activates the kinases TBK1 and RIPK1, which creates a branch in the signaling pathway. The TRIF/TBK1 signaling complex phosphorylates IRF3 allowing its translocation into the nucleus and production of Interferon type I. Meanwhile, activation of RIPK1 causes the polyubiquitination and activation of TAK1 and NFκB transcription in the same manner as the MyD88-dependent pathway.
TLR signaling ultimately leads to the induction or suppression of genes that orchestrate the inflammatory response. In all, thousands of genes are activated by TLR signaling, and collectively, the TLRs constitute one of the most pleiotropic yet tightly regulated gateways for gene modulation.
TLR4 is the only TLR that uses all four adaptors. Complex consisting of TLR4, MD2 and LPS recruits TIR domain-containing adaptors TIRAP and MyD88 and thus initiates activation of NFκB (early phase) and MAPK. TLR4-MD2-LPS complex then undergoes endocytosis and in endosome it forms a signalling complex with TRAM and TRIF adaptors. This TRIF-dependent pathway again leads to IRF3 activation and production of type I interferons, but it also activates late-phase NFκB activation. Both late and early phase activation of NFκB is required for production of inflammatory cytokines.
When microbes were first recognized as the cause of infectious diseases, it was immediately clear that multicellular organisms must be capable of recognizing them when infected and, hence, capable of recognizing molecules unique to microbes. A large body of literature, spanning most of the last century, attests to the search for the key molecules and their receptors. More than 100 years ago, Richard Pfeiffer, a student of Robert Koch, coined the term "endotoxin" to describe a substance produced by Gram-negative bacteria that could provoke fever and shock in experimental animals. In the decades that followed, endotoxin was chemically characterized and identified as a lipopolysaccharide (LPS) produced by most Gram-negative bacteria. This lipopolysaccharide is an integral part of the gram-negative membrane and is released upon destruction of the bacterium. Other molecules (bacterial lipopeptides, flagellin, and unmethylated DNA) were shown in turn to provoke host responses that are normally protective. However, these responses can be detrimental if they are excessively prolonged or intense. It followed logically that there must be receptors for such molecules, capable of alerting the host to the presence of infection, but these remained elusive for many years.
Toll-like receptors are now counted among the key molecules that alert the immune system to the presence of microbial infections. They are named for their similarity to toll, a receptor first identified in the fruit fly Drosophila melanogaster, and originally known for its developmental function in that organism. In 1996, toll was found by Jules A. Hoffmann and his colleagues to have an essential role in the fly's immunity to fungal infection, which it achieved by activating the synthesis of antimicrobial peptides. The plant homologs were discovered by Pamela Ronald in 1995 (rice XA21) and Thomas Boller in 2000 (Arabidopsis FLS2).
The first reported human toll-like receptor was described by Nomura and colleagues in 1994, mapped to a chromosome by Taguchi and colleagues in 1996. Because the immune function of toll in Drosophila was not then known, it was assumed that TIL (now known as TLR1) might participate in mammalian development. However, in 1991 (prior to the discovery of TIL) it was observed that a molecule with a clear role in immune function in mammals, the interleukin-1 (IL-1) receptor, also had homology to drosophila toll; the cytoplasmic portions of both molecules were similar.
In 1997, Charles Janeway and Ruslan Medzhitov showed that a toll-like receptor now known as TLR4 could, when artificially ligated using antibodies, induce the activation of certain genes necessary for initiating an adaptive immune response. TLR 4 function as an LPS sensing receptor was discovered by Bruce A. Beutler and colleagues. These workers used positional cloning to prove that mice that could not respond to LPS had mutations that abolished the function of TLR4. This identified TLR4 as one of the key components of the receptor for LPS.
In turn, the other TLR genes were ablated in mice by gene targeting, largely in the laboratory of Shizuo Akira and colleagues. Each TLR is now believed to detect a discrete collection of molecules – some of microbial origin, and some products of cell damage – and to signal the presence of infections.
Notes and references
- Mahla, RS (2013). "Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology.". Front Immunol. 2013 Sep 2;4:248. 4: 248. PMC . PMID 24032031. doi:10.3389/fimmu.2013.00248.
- Hansson GK, Edfeldt K (2005). "Toll to be paid at the gateway to the vessel wall". Arterioscler. Thromb. Vasc. Biol. 25 (6): 1085–7. PMID 15923538. doi:10.1161/01.ATV.0000168894.43759.47.
- Delneste Y, Beauvillain C, Jeannin P (2007). "Innate immunity: structure and function of TLRs". Med Sci (Paris). 23 (1): 67–73. PMID 17212934. doi:10.1051/medsci/200723167.
- Takeda, Kiyoshi; Akira, Shizuo (2005). "Toll-like receptors in innate immunity". International Immunology. 17 (1): 1–14. PMID 15585605. doi:10.1093/intimm/dxh186.
- Medzhitov R, Preston-Hurlburt P, Janeway C (1997). "A human homologue of the Drosophila Toll protein signals activation of adaptive immunity". Nature. 388 (6640): 394–7. PMID 9237759. doi:10.1038/41131.
- Sharma, N; et al. (2013). "Sphingosine-1-phosphate suppresses TLR-induced CXCL8 secretion from human T cells.". J Leukoc Biol. 93 (4): 521–528. PMID 23345392. doi:10.1189/jlb.0712328.
- Rolls A.; Shechter R.; London A.; et al. (September 2007). "Toll-like receptors modulate adult hippocampal neurogenesis". Nat. Cell Biol. 9 (9): 1081–8. PMID 17704767. doi:10.1038/ncb1629.
- Du X, Poltorak A, Wei Y, Beutler B (September 2000). "Three novel mammalian toll-like receptors: gene structure, expression, and evolution". Eur. Cytokine Netw. 11 (3): 362–71. PMID 11022119.
- Chuang TH, Ulevitch RJ (September 2000). "Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8 and hTLR9". Eur. Cytokine Netw. 11 (3): 372–8. PMID 11022120.
- Tabeta K, Georgel P, Janssen E; Georgel; Janssen; Du; Hoebe; Crozat; Mudd; Shamel; Sovath; Goode; Alexopoulou; Flavell; Beutler; et al. (March 2004). "Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection". Proc. Natl. Acad. Sci. U.S.A. 101 (10): 3516–21. Bibcode:2004PNAS..101.3516T. PMC . PMID 14993594. doi:10.1073/pnas.0400525101.
- Roach JC, Glusman G, Rowen L, Kaur A, Purcell MK, Smith KD, Hood LE, Aderem A; Glusman; Rowen; Kaur; Purcell; Smith; Hood; Aderem (2005). "The evolution of vertebrate Toll-like receptors" (PDF). Proc Natl Acad Sci USA. 102 (27): 9577–9582. Bibcode:2005PNAS..102.9577R. PMC . PMID 15976025. doi:10.1073/pnas.0502272102.
- Ferrandon D, Imler JL, Hetru C, Hoffmann JA (2007). "The Drosophila systemic immune response: sensing and signalling during bacterial and fungal infections". Nat Rev Immunol. 7 (11): 862–74. PMID 17948019. doi:10.1038/nri2194.
- Lee J; Sayed N; Hunter A; Au KF; Wong WH; Mocarski ES; et al. (2012). "Activation of innate immunity is required for efficient nuclear reprogramming". Cell. 151 (3): 547–58. PMC . PMID 23101625. doi:10.1016/j.cell.2012.09.034.
- Mathur R; Oh H; Zhang D; Park SG; Seo J; Koblansky A; et al. (2012). "A mouse model of Salmonella typhi infection". Cell. 151 (3): 590–602. PMC . PMID 23101627. doi:10.1016/j.cell.2012.08.042.
- Unless else specified in boxes then ref is: Waltenbaugh C, Doan T, Melvold R, Viselli S (2008). Immunology. Lippincott's Illustrated reviews. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 17. ISBN 0-7817-9543-5.
- Sabroe, Ian; Dower SK; Whyte MKB (2005). "The Role of Toll-Like Receptors in the Regulation of Neutrophil Migration, Activation, and Apoptosis". Clinical Infectious Diseases. 41 Suppl 7: S421–426. PMID 16237641. doi:10.1086/431992.
- Sallusto F, Lanzavecchia A (2002). "The instructive role of dendritic cells on T-cell responses". Arthritis Res. 4 Suppl 3: S127–32. PMC . PMID 12110131. doi:10.1186/ar567.
- Gerondakis, Steve; Grumont RJ; Banerjee A (2007). "Regulating B-cell activation and survival in response to TLR signals". Immunology and Cell Biology. 85 (6): 471–475. PMID 17637697. doi:10.1038/sj.icb.7100097.
- Cario, Elke; Rosenberg SL; Brandwein SL; Beck PL; Reinecker HC; Podolsky DK (2000). "Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing Toll-like receptors". J. Immunol. 164 (2): 966–972. PMID 10623846. doi:10.4049/jimmunol.164.2.966.
- Salazar Gonzalez RM, Shehata H, O'Connell MJ, Yang Y, Moreno-Fernandez ME, Chougnet CA, Aliberti J (2014). "Toxoplasma gondii- derived profilin triggers human toll-like receptor 5-dependent cytokine production". J Innate Immun. 6: 685–94. PMC . PMID 24861338. doi:10.1159/000362367.
- Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS, Hieny S, Sutterwala FS, Flavell RA, Ghosh S, Sher A (2005). "TLR11 activation of dendritic cells by a protozoan profilin-like protein". Science. 308 (5728): 1626–9. PMID 15860593. doi:10.1126/science.1109893.
- Pifer R, Benson A, Sturge CR and Yarovinsky F (November 2010). "UNC93B1 is essential for TLR11 activation and IL-12 dependent host resistance to Toxoplasma Gondii". Journal of Biological Chemistry. doi:10.1074/jbc.M110.171025 PMID 21097503
- Koblansky AA, Jankovic D, Oh H, Hieny S, Sungnak W, Mathur R, Hayden MS, Akira S, Sher A, Ghosh S (2012). "Recognition of Profilin by Toll-like Receptor 12 Is Critical for Host Resistance to Toxoplasma gondii". Immunity. 38 (1): 119–30. PMID 23246311. doi:10.1016/j.immuni.2012.09.016.
- Mishra BB, Gundra UM, Teale JM (2008). "Expression and distribution of Toll-like receptors 11-13 in the brain during murine neurocysticercosis". Journal of Neuroinflammation. 5: 53. PMC . PMID 19077284. doi:10.1186/1742-2094-5-53.
- Shi Z, Cai Z, Sanchez A, et al. (February 2011). "A novel Toll-like receptor that recognizes vesicular stomatitis virus". Journal of Biological Chemistry. 286 (6): 4517–24. PMC . PMID 21131352. doi:10.1074/jbc.M110.159590.
- Oldenburg M, Kruger A, Ferstl R; Krüger; Ferstl; Kaufmann; Nees; Sigmund; Bathke; Lauterbach; Suter; Dreher; Koedel; Akira; Kawai; Buer; Wagner; Bauer; Hochrein; Kirschning; et al. (August 2012). "TLR13 recognizes bacterial 23S rRNA devoid of erythromycin resistance-forming modification". Science. 337 (6098): 1111–5. Bibcode:2012Sci...337.1111O. PMID 22821982. doi:10.1126/science.1220363.
- Hoebe K, Du X, Georgel P; Du; Georgel; Janssen; Tabeta; Kim; Goode; Lin; Mann; Mudd; Crozat; Sovath; Han; Beutler; et al. (August 2003). "Identification of Lps2 as a key transducer of MyD88-independent TIR signalling". Nature. 424 (6950): 743–8. Bibcode:2003Natur.424..743H. PMID 12872135. doi:10.1038/nature01889.
- Hemmi H, Takeuchi O, Kawai T, et al. (December 2000). "A Toll-like receptor recognizes bacterial DNA". Nature. 408 (6813): 740–5. PMID 11130078. doi:10.1038/35047123.
- Kawai, Taro; Shizuo Akira (20 April 2010). "The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors". Nature Immunology. 11 (5): 373–384. doi:10.1038/ni.1863.
- Shigeoka AA, Holscher TD, King AJ, et al. (May 2007). "TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88-dependent and -independent pathways". J. Immunol. 178 (10): 6252–8. PMID 17475853. doi:10.4049/jimmunol.178.10.6252.
- Yamamoto M, Sato S, Hemmi H, et al. (November 2003). "TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway". Nat. Immunol. 4 (11): 1144–50. PMID 14556004. doi:10.1038/ni986.
- Yamamoto M, Sato S, Hemmi H; Sato; Hemmi; Sanjo; Uematsu; Kaisho; Hoshino; Takeuchi; Kobayashi; Fujita; Takeda; Akira; et al. (November 2002). "Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4". Nature. 420 (6913): 324–9. Bibcode:2002Natur.420..324Y. PMID 12447441. doi:10.1038/nature01182.
- Peter Fritsch (2004). Dermatologie Venerologie : Grundlagen. Klinik. Atlas. (in German). Berlin: Springer. ISBN 3-540-00332-0.
- Tidswell, M; Tillis, W; Larosa, SP; Lynn, M; Wittek, AE; Kao, R; Wheeler, J; Gogate, J; et al. (2010). "Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis". Critical Care Medicine. 38 (1): 72–83. PMID 19661804. doi:10.1097/CCM.0b013e3181b07b78.
- Toussi DN, Massari P Immune Adjuvant Effect of Molecularly-defined Toll-Like Receptor Ligands. Vaccines (Basel). 2014 Apr 25;2(2):323-53. PMID 26344622 PMC 4494261/
- Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA (September 1996). "The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults". Cell. 86 (6): 973–83. PMID 8808632. doi:10.1016/S0092-8674(00)80172-5.
- Song, W.Y.; Wang, G.-L.; Chen, L.-L.; Kim, H.-S.; Pi, L.-Y.; Holsten, T.; Gardner, J.; Wang, B.; Zhai, W.-X.; Zhu, L.-H.; Fauquet, C.; Ronald, P.; et al. (1995). "A receptor kinase-like protein encoded by the rice disease resistance gene, XA21". Science. 270 (5243): 1804–1806. Bibcode:1995Sci...270.1804S. PMID 8525370. doi:10.1126/science.270.5243.1804.
- Gomez-Gomez, L.; Boller, Thomas; et al. (2000). "FLS2: an LRR receptor-like kinase involved in the perception of the bacterial elicitor flagellin in Arabidopsis". Molecular Cell. 5 (6): 1003–1011. PMID 10911994. doi:10.1016/S1097-2765(00)80265-8.
- Nomura N, Miyajima N, Sazuka T, et al. (1994). "Prediction of the coding sequences of unidentified human genes. I. The coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of randomly sampled cDNA clones from human immature myeloid cell line KG-1" (– Scholar search). DNA Res. 1 (1): 27–35. PMID 7584026. doi:10.1093/dnares/1.1.27.[dead link]
- Taguchi T, Mitcham JL, Dower SK, Sims JE, Testa JR (March 1996). "Chromosomal localization of TIL, a gene encoding a protein related to the Drosophila transmembrane receptor Toll, to human chromosome 4p14". Genomics. 32 (3): 486–8. PMID 8838819. doi:10.1006/geno.1996.0150.
- Gay NJ, Keith FJ; Keith (May 1991). "Drosophila Toll and IL-1 receptor". Nature. 351 (6325): 355–6. Bibcode:1991Natur.351..355G. PMID 1851964. doi:10.1038/351355b0.
- Medzhitov R, Preston-Hurlburt P, Janeway CA (July 1997). "A human homologue of the Drosophila Toll protein signals activation of adaptive immunity". Nature. 388 (6640): 394–7. PMID 9237759. doi:10.1038/41131.
- Poltorak A, He X, Smirnova I; He; Smirnova; Liu; Van Huffel; Du; Birdwell; Alejos; Silva; Galanos; Freudenberg; Ricciardi-Castagnoli; Layton; Beutler; et al. (December 1998). "Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene". Science. 282 (5396): 2085–8. Bibcode:1998Sci...282.2085P. PMID 9851930. doi:10.1126/science.282.5396.2085.
- Mitchell, Bob (23 March 2011). "B.C. doctor wins prestigious medical prize". The Star.