Members of the toll-like family of receptors (nomenclature recommended by the NC-IUPHAR subcommittee on pattern recognition receptors, [2]) share significant homology with the interleukin-1 receptor family and appear to require dimerization either as homo- or heterodimers for functional activity. Heterodimerization appears to influence the potency of ligand binding substantially (e.g. TLR1/2 and TLR2/6, [18-19]). TLR1, TLR2, TLR4, TLR5, TLR6 and TLR11 are cell-surface proteins, while other members are associated with intracellular organelles, signalling through the MyD88-dependent pathways (with the exception of TLR3). As well as responding to exogenous infectious agents, it has been suggested that selected members of the family may be activated by endogenous ligands, such as hsp60 (HSPD1, P10809) [14].

* Key recommended reading is highlighted with an asterisk

* Bryant CE, Orr S, Ferguson B, Symmons MF, Boyle JP, Monie TP. (2015) International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease. Pharmacol. Rev., 67 (2): 462-504. [PMID:25829385]

* Goulopoulou S, McCarthy CG, Webb RC. (2016) Toll-like Receptors in the Vascular System: Sensing the Dangers Within. Pharmacol. Rev., 68 (1): 142-67. [PMID:26721702]

* Micera A, Balzamino BO, Di Zazzo A, Biamonte F, Sica G, Bonini S. (2016) Toll-Like Receptors and Tissue Remodeling: The Pro/Cons Recent Findings. J. Cell. Physiol., 231 (3): 531-44. [PMID:26248215]

* Zhang Z, Ohto U, Shimizu T. (2017) Toward a structural understanding of nucleic acid-sensing Toll-like receptors in the innate immune system. FEBS Lett., 591 (20): 3167-3181. [PMID:28686285]

* Zinngrebe J, Walczak H. (2017) TLRs Go Linear - On the Ubiquitin Edge. Trends Mol Med, 23 (4): 296-309. [PMID:28325627]

1. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature, 413 (6857): 732-8. [PMID:11607032]

2. Bryant CE, Orr S, Ferguson B, Symmons MF, Boyle JP, Monie TP. (2015) International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease. Pharmacol. Rev., 67 (2): 462-504. [PMID:25829385]

3. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A. (2001) The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature, 410 (6832): 1099-103. [PMID:11323673]

4. Heil F, Ahmad-Nejad P, Hemmi H, Hochrein H, Ampenberger F, Gellert T, Dietrich H, Lipford G, Takeda K, Akira S et al.. (2003) The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur. J. Immunol., 33 (11): 2987-97. [PMID:14579267]

5. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S. (2002) Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol., 3 (2): 196-200. [PMID:11812998]

6. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K et al.. (2000) A Toll-like receptor recognizes bacterial DNA. Nature, 408 (6813): 740-5. [PMID:11130078]

7. Huynh AS, Chung WJ, Cho HI, Moberg VE, Celis E, Morse DL, Vagner J. (2012) Novel toll-like receptor 2 ligands for targeted pancreatic cancer imaging and immunotherapy. J. Med. Chem., 55 (22): 9751-62. [PMID:23098072]

8. Ii M, Matsunaga N, Hazeki K, Nakamura K, Takashima K, Seya T, Hazeki O, Kitazaki T, Iizawa Y. (2006) A novel cyclohexene derivative, ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol. Pharmacol., 69 (4): 1288-95. [PMID:16373689]

9. Ingalls RR, Monks BG, Savedra R, Christ WJ, Delude RL, Medvedev AE, Espevik T, Golenbock DT. (1998) CD11/CD18 and CD14 share a common lipid A signaling pathway. J. Immunol., 161 (10): 5413-20. [PMID:9820516]

10. Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, Lipford G, Bauer S. (2002) Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat. Immunol., 3 (6): 499. [PMID:12032557]

11. Kawasaki K, Akashi S, Shimazu R, Yoshida T, Miyake K, Nishijima M. (2000) Mouse toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J. Biol. Chem., 275 (4): 2251-4. [PMID:10644670]

12. Lamphier M, Zheng W, Latz E, Spyvee M, Hansen H, Rose J, Genest M, Yang H, Shaffer C, Zhao Y et al.. (2014) Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo. Mol. Pharmacol., 85 (3): 429-40. [PMID:24342772]

13. Larson P, Kucaba TA, Xiong Z, Olin M, Griffith TS, Ferguson DM. (2017) Design and Synthesis of N1-Modified Imidazoquinoline Agonists for Selective Activation of Toll-like Receptors 7 and 8. ACS Med. Chem. Lett., Epub ahead of print.

14. Ohashi K, Burkart V, Flohé S, Kolb H. (2000) Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J. Immunol., 164 (2): 558-61. [PMID:10623794]

15. Oosting M, Cheng SC, Bolscher JM, Vestering-Stenger R, Plantinga TS, Verschueren IC, Arts P, Garritsen A, van Eenennaam H, Sturm P et al.. (2014) Human TLR10 is an anti-inflammatory pattern-recognition receptor. Proc. Natl. Acad. Sci. U.S.A., 111 (42): E4478-84. [PMID:25288745]

16. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C et al.. (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science, 282 (5396): 2085-8. [PMID:9851930]

17. Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning CJ. (1999) Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J. Biol. Chem., 274 (25): 17406-9. [PMID:10364168]

18. Takeuchi O, Kawai T, Mühlradt PF, Morr M, Radolf JD, Zychlinsky A, Takeda K, Akira S. (2001) Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol., 13 (7): 933-40. [PMID:11431423]

19. Takeuchi O, Sato S, Horiuchi T, Hoshino K, Takeda K, Dong Z, Modlin RL, Akira S. (2002) Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol., 169 (1): 10-4. [PMID:12077222]

20. Yoshimura A, Lien E, Ingalls RR, Tuomanen E, Dziarski R, Golenbock D. (1999) Cutting edge: recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2. J. Immunol., 163 (1): 1-5. [PMID:10384090]

Clare Bryant Professor of Innate Immunity The Department of Veterinary Medicine The University of Cambridge Madingley Road Cambridge, UK, CB3 0ES UK Tom Monie The Department of Veterinary Medicine The University of Cambridge Madingley Road Cambridge CB3 0ES UK