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TLR Signaling

  • Chapter
From Innate Immunity to Immunological Memory

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 311))

Abstract

Mammalian Toll-like receptors (TLRs) play a critical role in detection of invading pathogens as well as triggering of subsequent inflammatory and immune responses. Each TLR recognizes distinct microbial components and activates different signaling pathways by selective utilization of adaptor molecules. The signaling via TLRs is delivered from the cell surface and/or the endosome. Recently, the intracytoplasmic detection system of microbes has been identified in mammals as well. Peptidoglycan breakdown products and double-stranded RNA are sensed by NOD family and RNA helicase domain containing proteins, respectively. Thus, mammals make use of both receptor-type and intracellular proteins as detectors of invading pathogens.

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References

  • Adachi O, Kawai T, Takeda K, Matsumoto M, Tsutsui H, Sakagami M, Nakanishi K, Akira S (1998) Targeted disruption of the MyD 88 gene results in loss of IL-1-and IL-18-mediated function. Immunity 9:143–150

    Article  PubMed  CAS  Google Scholar 

  • Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511

    Article  PubMed  CAS  Google Scholar 

  • Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413:732–738

    Article  PubMed  CAS  Google Scholar 

  • Beutler B (2004) Inferences, questions and possibilities in Toll-like receptor signalling. Nature 430:257–263

    Article  PubMed  CAS  Google Scholar 

  • Bonnard M, Mirtsos C, Suzuki S, Graham K, Huang J, Ng M, Itie A, Wakeham A, Shahinian A, Henzel WJ, Elia AJ, Shillinglaw W, Mak TW, Cao Z, Yeh WC (2000) Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappa B-dependent gene transcription. EMBO J 19:4976–4985

    Article  PubMed  CAS  Google Scholar 

  • Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, Ogura Y, Kawasaki A, Fukase K, Kusumoto S, Valvano MA, Foster SJ, Mak TW, Nunez G, Inohara N (2003) An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol 4:702–707

    Article  PubMed  CAS  Google Scholar 

  • Coban C, Ishii KJ, Kawai T, Hemmi H, Sato S, Uematsu S, Yamamoto M, Takeuchi O, Itagaki S, Kumar N, Horii T, Akira S (2005) Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J Exp Med 201:19–25

    Article  PubMed  CAS  Google Scholar 

  • Colonna M, Trinchieri G, Liu YJ (2004) Plasmacytoid dendritic cells in immunity. Nat Immunol 5:1219–1226

    Article  PubMed  CAS  Google Scholar 

  • Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies C, Mansell AS, Brady G, Brint E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O’Neill LA (2001) Mal (MyD88-adaptor-like) is required for Toll-like receptor-4 signal transduction. Nature 413:78–83

    Article  PubMed  CAS  Google Scholar 

  • Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM, Maniatis T (2003) IKKε and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 4:491–496

    Article  PubMed  CAS  Google Scholar 

  • Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jehanno M, Viala J, Tedin K, Taha MK, Labigne A, Zahringer U, Coyle AJ, DiStefano PS, Bertin J, Sansonetti PJ, Philpott DJ (2003a) Nod1 detects a unique muropeptide from Gram-negative bacterial peptidoglycan. Science 300:1584–1587

    Article  PubMed  CAS  Google Scholar 

  • Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, Philpott DJ, Sansonetti PJ (2003b) Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278:8869–8872

    Article  PubMed  CAS  Google Scholar 

  • Hemmi H, Takeuchi O, Sato S, Yamamoto M, Kaisho T, Sanjo H, Kawai T, Hoshino K, Takeda K, Akira S (2004) The roles of two IκB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J Exp Med 199:1641–1650

    Article  PubMed  CAS  Google Scholar 

  • Hoebe K, Du X, Georgel P, Janssen E, Tabeta K, Kim SO, Goode J, Lin P, Mann N, Mudd S, Crozat K, Sovath S, Han J, Beutler B (2003) Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424:743–748

    Article  PubMed  CAS  Google Scholar 

  • Honda K, Yanai H, Mizutani T, Negishi H, Shimada N, Suzuki N, Ohba Y, Takaoka A, Yeh WC, Taniguchi T (2004) Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc Natl Acad Sci USA 101:15416–15421

    Article  PubMed  CAS  Google Scholar 

  • Horng T, Barton GM, Medzhitov R (2001) TIRAP: an adapter molecule in the Toll signaling pathway. Nat Immunol 2:835–841

    Article  PubMed  CAS  Google Scholar 

  • Horng T, Barton GM, Flavell RA, Medzhitov R (2002) The adaptor molecule TIRAP provides signaling specificity for Toll-like receptors. Nature 420:329–333

    Article  PubMed  CAS  Google Scholar 

  • Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599–603

    Article  PubMed  CAS  Google Scholar 

  • Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, Fukase K, Inamura S, Kusumoto S, Hashimoto M, Foster SJ, Moran AP, Fernandez-Luna JL, Nunez G (2003) Host recognition of bacterial muramyl dipeptide mediated through NOD2: implications for Crohn’s disease. J Biol Chem 278:5509–5512

    Article  PubMed  CAS  Google Scholar 

  • Kang D, Gopalkrishnan RV, Wu Q, Jankowsky E, Pyle AM, Fisher PB (2002) Mda5: an interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties. Proc Natl Acad Sci USA 99:637–642

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Kawai T, Takeuchi O, Fujita T, Inoue J, Mühlradt PF, Sato S, Hoshino K, Akira S (2001) Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IRF-3 and the expression of a subset of LPS-inducible genes. J Immunol 167:5887–6894

    PubMed  CAS  Google Scholar 

  • Kawai T, Sato S, Ishii KJ, Coban C, Hemmi H, Yamamoto M, Terai K, Matsuda M, Inoue J, Uematsu S, Takeuchi O, Akira S (2004) Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 10:1118–1126

    Google Scholar 

  • Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA (1996) The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983

    Article  PubMed  CAS  Google Scholar 

  • Maeda S, Hsu LC, Liu H, Bankston LA, Iimura M, Kagnoff MF, Eckmann L, Karin M (2005) Nod2 mutation in Crohn’s disease potentiates NF-κB activity and IL-1β processing. Science 307:734–738

    Article  PubMed  CAS  Google Scholar 

  • McWhirter SM, Fitzgerald KA, Rosains J, Rowe DC, Golenbock DT, Maniatis T (2004) IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts. Proc Natl Acad Sci U S A 101:233–238

    Article  PubMed  CAS  Google Scholar 

  • Medzhitov R (2001) Toll-like receptors and innate immunity. Nat Rev Immunol 1:135–145

    Article  PubMed  CAS  Google Scholar 

  • Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–397

    Article  PubMed  CAS  Google Scholar 

  • Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, Tschopp J (2004) RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nat Immunol 5:503–507

    Article  PubMed  CAS  Google Scholar 

  • Miceli-Richard C, Lesage S, Rybojad M, Prieur AM, Manouvrier-Hanu S, Hafner R, Chamaillard M, Zouali H, Thomas G, Hugot JP (2001) CARD15 mutations in Blau syndrome. Nat Genet 29:19–20

    Article  PubMed  CAS  Google Scholar 

  • Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nunez G, Cho JH (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603–606

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K, Akira S (2003) Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J Immunol 171:4304–4310

    PubMed  CAS  Google Scholar 

  • Sharma S, tenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J (2003) Triggering the interferon antiviral response through an IKK-related pathway. Science 300:1148–1151

    Article  PubMed  CAS  Google Scholar 

  • Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi O, Takeda K, Hoshino K, Adachi O, Ogawa T, Akira S (2000) Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signaling cascades. Int Immunol 12:113–117

    Article  PubMed  CAS  Google Scholar 

  • Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, Takeshita F, Matsuda M, Coban C, Ishii KJ, Kawai T, Takeuchi O, Akira S (2006) Interleukin-1 receptor-associated kinase-1 plays an essential role for TLR7-and TLR9-mediated interferon-α induction. J Exp Med 201:915–923

    Article  Google Scholar 

  • Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, Kaisho T, Hoshino K, Takeuchi O, Kobayashi M, Fujita T, Takeda K, Akira S (2002a) Essential role of TIRAP/Mal for activation of the signaling cascade shared by TLR2 and TLR4. Nature 420:324–329

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto M, Sato S, Mori K, Takeuchi O, Hoshino K, Takeda K, Akira S (2002b) A novel TIR domain-containing adaptor that preferentially activates the interferon-β promoter. J Immunol 169:6668–6672

    PubMed  CAS  Google Scholar 

  • Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, Akira S (2003a) Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301:640–643

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, Takeuchi O, Takeda K, Akira S (2003b) TRAM is specifically involved in the TLR4-mediated MyD88-independent signaling pathway. Nat Immunol 4:1144–1150

    Article  PubMed  CAS  Google Scholar 

  • Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T (2004) The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5:730–737

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University and ERATO, JST, 3-1 Yamadaoka, Suita, 565-00, Osaka, Japan

    S. Akira

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  1. S. Akira
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Editor information

Editors and Affiliations

  1. Emory Vaccine Center, 954 Gatewood Road, Atlante, GA, 30329, USA

    Bali Pulendran Ph.D.  & Rafi Ahmed Ph.D.  & 

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© 2006 Springer-Verlag Berlin Heidelberg

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Akira, S. (2006). TLR Signaling. In: Pulendran, B., Ahmed, R. (eds) From Innate Immunity to Immunological Memory. Current Topics in Microbiology and Immunology, vol 311. Springer, Berlin, Heidelberg . https://doi.org/10.1007/3-540-32636-7_1

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