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Definition: Toll-like receptors (TLRs) are homologous to a Drosophila protein called Toll. 10 mammalian TLRs have been identified in 2005.

Toll-like receptors (TLRs) have an important role in innate immunity in mammals by recognizing conserved microbial components that are known as pathogen-associated molecular patterns (PAMPs).

Although the majority of these receptors sense pathogen components on the cell surface, a subset of them (TLR3, TLR7, TLR8 and TLR9) senses viral and bacterial nucleic acids in endosomal compartments.

Of considerable interest is the recent finding that TLR7 and TLR8 can also recognize small interfering RNA (siRNA), which is the main effector in RNA interference. This immune activation by siRNAs can be abrogated by the 2’-ribose modification of uridines.

 TLRs function to activate leukocytes in response to different types and components of microbes.

 TLRs appear to be required for responses to different classes of infectious pathogens.

 Different TLRs play essential roles in cellular responses to bacterial lipopolysaccharide (LPS, or endotoxin), other bacterial proteoglycans, and unmethylated CpG nucleotides, all of which are found only in bacteria, as well as double-stranded RNA, which is produced only by some viruses.

 TLRs function by receptor-associated kinases to stimulate the production of microbicidal substances and cytokines in the leukocytes.

Members

 TLR2 recognizes various PAMPs, including peptidoglycan from Gram-positive bacteria, lipoarabinomannan from mycobacteria, hemagglutinin protein from measles virus and tGPI-mutin from Trypanosoma.

 TLR2/1 and TLR2/6 discriminate the lipid structures between triacyl- and diacyl-lipopeptide, respectively.

 TLR2/6 also recognizes zymosan from Saccharomyces cerevisiae (S. cerevisiae).

 TLR4 recognizes bacterial LPS and synthetic MPLA as well as envelope proteins from respiratory syncytial virus (RSV) and mouse mammary tumor virus (MMTV).

 TLR5 detects bacterial flagellin expressed in intestinal epithelial cells as well as CD11c-positive lamina propria in DCs.

 In mice, TLR11 recognizes as yet unknown components of uropathogenic bacteria, and a profilin-like molecule of Toxoplasma gondii.

 TLR3, 7, 8 and 9, which are localized to endosomes, detect nucleic acids derived from viruses and bacteria.

 TLR3 recognizes dsRNA, which is produced by many viruses during replication, and poly IC.

= TLR7 recognizes ssRNA derived from various viruses and synthetic imidazoquinolines with antitumor properties.

 Human TLR8 also participates in the recognition of ssRNA and imidazoquinolines, whereas the function of mouse TLR8 remains unclear.

 TLR9 recognizes CpG DNA motifs present in bacterial and viral genomes as well as non-nucleic acids such as hemozoin from Plasmodium.

 TLR1, 2 and 6 utilize MyD88 and TIRAP as adaptors while TLR5, 7, 9 and 11 utilize MyD88.

 TLR4 uses four adaptors, MyD88, TIRAP, TRIF and TRAM.

 TLR3 uses TRIF as the sole adaptor.

TLR signaling pathway

 TLR2-, TLR3- and TLR4-mediated signaling.

• TLR4 activates both the MyD88- and the TRIF-dependent pathways. TIRAP and TRAM are required for the activation of the MyD88- and the TRIF-dependent pathways, respectively.
• MyD88 recruits TRAF6 and members of the IRAK family. TRAF6, together with Ubc13 and Uev1A, activates the TAK1 complex via K63-linked ubiquitination (Ub).
• The activated TAK1 complex then activates the IKK complex consisting of IKKα, IKKβ and NEMO, which catalyzes the phosphorylation of IκB proteins (P).
• IκBs are destroyed by the proteasome-dependent pathway, allowing NF-κB (RelA-p50 heterodimer) to translocate into the nucleus (canonical pathway).
• Simultaneously, the TAK1 complex activates the MAPK pathway, which results in the phosphorylation (P) and activation of AP-1.
• NF-κB and AP-1 control inflammatory responses through the induction of inflammatory cytokines. TRIF recruits TRAF3, which then interacts with TBK1 and IKKi. These kinases mediate phosphorylation of IRF3 (P).
• Phosphorylated IRF3 dimerizes and translocates into the nucleus to regulate transcription.
• TRIF also interacts with TRAF6 and RIP1, which mediate NF-κB activation.
• Activation of the IRF3, NF-κB and MAPK pathways is required for induction of type I IFN, particularly IFN-β.
• There are two types of NF-κB activation in TLR4 signaling: the MyD88-dependent pathway, which mediates early phase activation of NF-κB and the TRIF-dependent pathway, which mediates the late phase activation of NF-κB.
• TLR3, which resides in endosomal vesicles, utilizes TRIF, whereas TLR2 utilizes TIRAP and MyD88.

See also

 TLR signaling pathways

• TLR signaling pathway diseases

References

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 Kawai T, Akira S. Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med. 2007 Oct 26; PMID: #18029230#

 Liu PT, Krutzik SR, Modlin RL. Therapeutic implications of the TLR and VDR partnership. Trends Mol Med. 2007 Feb 2; PMID: #17276732#

 Sioud M. Innate sensing of self and non-self RNAs by Toll-like receptors. Trends Mol Med. 2006 Apr;12(4):167-76. PMID: #16530484#

 Puel A, Yang K, Ku CL, von Bernuth H, Bustamante J, Santos OF, Lawrence T, Chang HH, Al-Mousa H, Picard C, Casanova JL. Heritable defects of the human TLR signalling pathways. J Endotoxin Res. 2005;11(4):220-4. PMID: #16176658#

 Brunn GJ, Platt JL. The etiology of sepsis: turned inside out. Trends Mol Med. 2005 Nov 17; PMID: #16298551#

 Guerau-de-Arellano M, Huber BT. Chemokines and Toll-like receptors in Lyme disease pathogenesis. Trends Mol Med. 2005 Mar;11(3):114-20. PMID: #15760769#

 Netea MG, Van der Meer JW, Kullberg BJ. Toll-like receptors as an escape mechanism from the host defense. Trends Microbiol. 2004 Nov;12(11):484-488. PMID: #15488388#

 Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004 Oct;5(10):987-95. PMID: #15454922#

 Cook DN, Pisetsky DS, Schwartz DA. Toll-like receptors in the pathogenesis of human disease. Nat Immunol. 2004 Oct;5(10):975-9. PMID: #15454920#

 Clevers H. At the crossroads of inflammation and cancer. Cell. 2004 Sep 17;118(6):671-4. PMID: #15369667#

 Goldstein DR. Toll-like receptors and other links between innate and acquired alloimmunity. Curr Opin Immunol. 2004 Oct;16(5):538-44. PMID: #15341996#

 Kaisho T, Akira S. Regulation of dendritic cell function through toll-like receptors. Curr Mol Med. 2003 Dec;3(8):759-71. PMID: #14682496#