Evolution and integration of innate immune recognition systems: the Toll-like receptors

Abstract

Toll-like receptors (TLRs) recognize specific components of micro-organisms and trigger the activation of innate immunity. TLR-mediated signaling pathways are now rapidly being elucidated. TLR signaling originates from the cytoplasmic Toll/IL-1 receptor (TIR) domain, which is conserved among all TLRs. Furthermore, TIR domain-containing adaptors, such as MyD88, TRIF, TIRAP and TRAM, play essential roles in TLR signaling. MyD88 is essential for inflammatory cytokine production via all TLRs, whereas TRIF is involved in TLR3- and TLR4-mediated MyD88-independent induction of IFN-β. Thus, innate immunity represents a skilful system that senses microbial invasion and initiates appropriate immune responses.

Keywords

Toll-like receptors (TLRs)innate immune recognition TLR signaling pathways TRIF review

References

Lemaitre B. , Nicolas E. , Michaut L. , Reichhart J-M. , Hoffmann JA The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996; 86: 973—983.

Takeda K. , Kaisho T. , Akira S. Toll-like receptors. Annu Rev Immunol 2003 ; 21: 335—376.

Janeway Jr CA , Medzhitov R. Innate immune recognition. Annu Rev Immunol 2002; 20: 197—216.

Poltorak A. , He X. , Smirnova I. , Liu MY et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutation in Tlr4 gene. Science 1998; 282: 2085—2088.

Hoshino K. , Takeuchi O. , Kawai T. et al. Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 1999; 162: 3749—3752.

Akira S. , Takeda K. Toll-like receptor signaling. Nat Rev Immunol 2004; 4: 499—511.

Kawai T. , Adachi O. , Ogawa T. , Takeda K. , Akira S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 1999; 11: 115—122.

Kawai T. , Takeuchi O. , Fujita T. et al. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IRF-3 and the expression of a subset of LPSinducible genes. J Immunol 2001; 167: 5887—5894.

Doyle SE , Vaidya SA , O'Connell R. et al. IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 2002; 17: 251—263.

10.

Toshchakov V. , Jones BW , Perera PY et al. TLR4, but not TLR2, mediates IFN-β-induced STAT1α/β-dependent gene expression in macrophages. Nat Immunol 2002; 3: 392—398.

11.

Hoshino K. , Kaisho T. , Iwabe T. , Takeuchi O. , Akira S. Differential involvement of IFN-β in Toll-like receptor-stimulated dendritic cell activation. Int Immunol 2002; 14: 1225—1231.

12.

Sharma S. , tenOever BR , Grandvaux N. , Zhou GP , Lin R. , Hiscott J. Triggering the interferon antiviral response through an IKKrelated pathway . Science 2003; 300: 1148—1151.

13.

Shimada T. , Kawai T. , Takeda K. et al. IKK-i, a novel lipopolysaccharide-inducible kinase that is related to IκB kinases. Int Immunol 1999; 11: 1357—1362.

14.

Pomerantz JL , Baltimore D. NF-κB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKKrelated kinase. EMBO J 1999; 18: 6694—6704.

15.

Peters RT , Liao SM , Maniatis T. IKKε is part of a novel PMAinducible IκB kinase complex. Mol Cell 2000; 5: 513—522.

16.

Fitzgerald KA , McWhirter SM , Faia KL et al. IKKε and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 2003; 4: 491—496.

17.

McWhirter SM , Fitzgerald KA , Rosains J. , Rowe DC , Golenbock DT , Maniatis T. IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts. Proc Natl Acad Sci USA 2004; 101: 233—238.

18.

Hemmi H. , Takeuchi O. , Sato S. et al. The roles of two IκB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J Exp Med 2004; 199: 1641—1650.

19.

Perry AK , Chow EK , Goodnough JB , Yeh WC , Cheng G. Differential requirement for TANK-binding kinase-1 in type I interferon responses to Toll-like receptor activation and viral infection. J Exp Med 2004; 199: 1651—1658.

20.

Yamamoto M. , Sato S. , Mori K. et al. A novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-β promoter in the Toll-like receptor signaling. J Immunol 2002; 169: 6668—6672.

21.

Oshiumi H. , Matsumoto M. , Funami K. , Akazawa T. , Seya T. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-β induction. Nat Immunol 2003 ; 4: 161—167.

22.

Yamamoto M. , Sato S. , Hemmi H. et al. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 2003; 301: 640—643.

23.

Hoebe K. , Du X. , Georgel P. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 2003; 424: 743—748.

24.

Sato S. , Sugiyama M. , Yamamoto M. et al. Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-κB and IFN-regulatory factor-3, in the Toll-like receptor signaling. J Immunol 2003; 171: 4304—4310.

25.

Jiang Z. , Mak TW , Sen G. , Li X. Toll-like receptor 3-mediated activation of NF-κB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-β. Proc Natl Acad Sci USA 2004; 101: 3533—3538.

26.

Meylan E. , Burns K. , Hofmann K. et al. RIP1 is an essential mediator of Toll-like receptor 3-induced NF-κB activation. Nat Immunol 2004; 5: 503—507.

27.

Horng T. , Barton GM , Flavell RA , Medzhitov R. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors . Nature 2002; 420: 329—333.

28.

Yamamoto M. , Sato S. , Hemmi H. et al. Essential role of TIRAP/Mal for activation of the signaling cascade shared by TLR2 and TLR4. Nature 2002; 420: 324—329.

29.

Oshiumi H. , Sasai M. , Shida K. , Fujita T. , Matsumoto M. , Seya T. TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to Toll-like receptor 4 TICAM-1 that induces interferon-β. J Biol Chem 2003; 278: 49751—49762.

30.

Fitzgerald KA , Rowe DC , Barnes BJ et al. LPS-TLR4 signaling to IRF-3/7 and NF-κB involves the Toll adapters TRAM and TRIF. J Exp Med 2003; 198: 1043—1055.

31.

Yamamoto M. , Sato S. , Hemmi H. et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 2003; 4: 1144—1150.

32.

Nagai Y. , Akashi S. , Nagafuku M. et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution . Nat Immunol 2002; 3: 667—672.

33.

Gantner BN , Simmons RM , Canavera SJ , Akira S. , Underhill DM Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J Exp Med 2003; 197: 1107—1117.

34.

Kobayashi M. , Kweon M. , Kuwata H. , Kiyono H. , Takeda K. , Akira S. Toll-like receptor-dependent IL-12p40 production causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice . J Clin Invest 2003; 111: 1297—1308.

35.

Bjorkbacka H. , Kunjathoor VV , Moore KJ et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med 2004; 10: 416—421.

36.

Michelsen KS , Wong MH , Shah PK et al. 2004. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci USA 2004; 101: 10679—10684.