Abstract
The Toll-like receptors (TLRs) are the key proteins that allow mammals — whether immunologically naive or experienced — to detect microbes. They lie at the core of our inherited resistance to disease, initiating most of the phenomena that occur in the course of infection. Quasi-infectious stimuli that have been used for decades to study inflammatory mechanisms can activate the TLR family of proteins. And it now seems that many inflammatory processes, both sterile and infectious, may depend on TLR signalling. We are in a good position to apply our understanding of TLR signalling to a range of challenges in immunology and medicine.
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References
Anderson, K. V., Bokla, L. & Nusslein-Volhard, C. Establishment of dorsal–ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product. Cell 42, 791–798 (1985).
Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J. M. & Hoffmann, J. A. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973–983 (1996).
Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).
Tabeta, K. et al. TLR9 and TLR3 as essential components of innate immune defense against mouse cytomegalovirus. Proc. Natl Acad. Sci. USA 101, 3516–3521 (2004).
Beutler, B., Hoebe, K., Georgel, P., Tabeta, K. & Du, X. Forward genetic dissection of afferent immunity: the role of TIR adapter proteins in innate and adaptive immune responses. Adv. Exp. Med. Biol. (in the press).
Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nature Immunol. 2, 675–680 (2001).
Campos, M. A. et al. Activation of Toll-like receptor-2 by glycosylphosphatidylinositol anchors from a protozoan parasite. J. Immunol. 167, 416–423 (2001).
Campos, M. A. et al. Impaired production of proinflammatory cytokines and host resistance to acute infection with Trypanosoma cruzi in mice lacking functional myeloid differentiation factor 88. J. Immunol. 172, 1711–1718 (2004).
Underhill, D. M. et al. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401, 811–815 (1999).
Takeuchi, O. et al. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components. Immunity 11, 443–451 (1999).
Hayashi, F. et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099–1103 (2001).
Zhang, D. et al. A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303, 1522–1526 (2004).
Meier, A. et al. Toll-like receptor (TLR) 2 and TLR4 are essential for Aspergillus-induced activation of murine macrophages. Cell Microbiol. 5, 561–570 (2003).
Hoebe, K. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424, 743–748 (2003).
Lund, J., Sato, A., Akira, S., Medzhitov, R. & Iwasaki, A. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J. Exp. Med. 198, 513–520 (2003).
Heil, F. et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303, 1526–1529 (2004).
Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004).
Lund, J. M. et al. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl Acad. Sci. USA 101, 5598–5603 (2004).
Chamaillard, M., Girardin, S. E., Viala, J. & Philpott, D. J. Nods, Nalps and Naip: intracellular regulators of bacterial-induced inflammation. Cell Microbiol. 5, 581–592 (2003).
Brown, M. G. et al. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292, 934–937 (2001).
Hoebe, K. et al. Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways. Nature Immunol. 4, 1223–1229 (2003).
Schnare, M. et al. Toll-like receptors control activation of adaptive immune responses. Nature Immunol. 2, 947–950 (2001).
Beutler, B. et al. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 316, 552–554 (1985).
Beutler, B., Milsark, I. W. & Cerami, A. Passive immunization against cachectin/tumor necrosis factor (TNF) protects mice from the lethal effect of endotoxin. Science 229, 869–871 (1985).
Car, B. D. et al. Interferon γ receptor deficient mice are resistant to endotoxic shock. J. Exp. Med. 179, 1437–1444 (1994).
Karaghiosoff, M. et al. Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock. Nature Immunol. 4, 471–477 (2003).
Wysocka, M. et al. Interleukin-12 is required for interferon-γ production and lethality in lipopolysaccharide-induced shock in mice. Eur. J. Immunol. 25, 672–676 (1995).
Elliott, M. J. et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis. Lancet 344, 1105–1110 (1994).
Brandt, J. et al. Successful treatment of active ankylosing spondylitis with the anti-tumor necrosis factor α monoclonal antibody infliximab. Arthritis Rheum. 43, 1346–1352 (2000).
Van Dullemen, H. M. et al. Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 109, 129–135 (1995).
Iyer, S., Yamauchi, P. & Lowe, N. J. Etanercept for severe psoriasis and psoriatic arthritis: observations on combination therapy. Br. J. Dermatol. 146, 118–121 (2002).
Georgel, P. et al. Drosophila immune deficiency (IMD) is a death domain protein that activates antibacterial defense and can promote apoptosis. Dev. Cell 1, 503–514 (2001).
Sun, S. C., Lindstrom, I., Lee, J. Y. & Faye, I. Structure and expression of the attacin genes in Hyalophora cecropia. Eur. J. Biochem. 196, 247–254 (1991).
Reichhart, J. M. et al. Insect immunity: developmental and inducible activity of the Drosophila diptericin promoter. EMBO J. 11, 1469–1477 (1992).
Georgel, P. et al. Insect immunity: the diptericin promoter contains multiple functional regulatory sequences homologous to mammalian acute-phase response elements. Biochem. Biophys. Res. Commun. 197, 508–517 (1993).
Rutschmann, S. et al. The Rel protein DIF mediates the antifungal but not the antibacterial host defense in Drosophila. Immunity 12, 569–580 (2000).
Shakhov, A. N., Collart, M. A., Vassalli, P., Nedospasov, S. A. & Jongeneel, C. V. κB-type enhancers are involved in lipopolysaccharide-mediated transcriptional activation of the tumor necrosis factor α gene in primary macrophages. J. Exp. Med. 171, 35–47 (1990).
Han, J., Brown, T. & Beutler, B. Endotoxin-responsive sequences control cachectin/TNF biosynthesis at the translational level. J. Exp. Med. 171, 465–475 (1990).
Hsu, H. L., Shu, H. B., Pan, M. G. & Goeddel, D. V. TRADD–TRAF2 and TRADD–FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84, 299–308 (1996).
Rothe, M., Sarma, V., Dixit, V. W. & Goeddel, D. V. TRAF2-mediated activation of NF-κB by TNF receptor 2 and CD40. Science 269, 1424–1427 (1995).
Han, S. H., Yea, S. S., Jeon, Y. J., Yang, K. H. & Kaminski, N. E. Transforming growth factor-β1 (TGF-β1) promotes IL-2 mRNA expression through the up-regulation of NF-κB, AP-1 and NF-AT in EL4 cells. J. Pharmacol. Exp. Ther. 287, 1105–1112 (1998).
Arsura, M. et al. Transient activation of NF-κB through a TAK1/IKK kinase pathway by TGF-β1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation. Oncogene 22, 412–425 (2003).
Sakurai, H., Chiba, H., Miyoshi, H., Sugita, T. & Toriumi, W. IκB kinases phosphorylate NF-κB p65 subunit on serine 536 in the transactivation domain. J. Biol. Chem. 274, 30353–30356 (1999).
Sakurai, H., Miyoshi, H., Toriumi, W. & Sugita, T. Functional interactions of transforming growth factor β-activated kinase 1 with IκB kinases to stimulate NF-κB activation. J. Biol. Chem. 274, 10641–10648 (1999).
Goldfeld, A. E. et al. Calcineurin mediates human tumor necrosis factor α gene induction in stimulated T and B cells. J. Exp. Med. 180, 763–768 (1994).
Verweij, C. L., Geerts, M. & Aarden, L. A. Activation of interleukin-2 gene transcription via the T-cell surface molecule CD28 is mediated through an NF-κB-like response element. J. Biol. Chem. 266, 14179–14182 (1991).
Harhaj, E. W., Maggirwar, S. B., Good, L. & Sun, S. C. CD28 mediates a potent costimulatory signal for rapid degradation of IκBβ which is associated with accelerated activation of various NF-κB/Rel heterodimers. Mol. Cell. Biol. 16, 6736–6743 (1996).
Hehner, S. P. et al. Mixed-lineage kinase 3 delivers CD3/CD28-derived signals into the IκB kinase complex. Mol. Cell. Biol. 20, 2556–2568 (2000).
Lin, X., O'Mahony, A., Mu, Y., Geleziunas, R. & Greene, W. C. Protein kinase C-Θ participates in NF-κB activation induced by CD3–CD28 costimulation through selective activation of IκB kinase β. Mol. Cell. Biol. 20, 2933–2940 (2000).
Jun, J. E. et al. Identifying the MAGUK protein Carma-1 as a central regulator of humoral immune responses and atopy by genome-wide mouse mutagenesis. Immunity 18, 751–762 (2003).
Marinari, B., Costanzo, A., Marzano, V., Piccolella, E. & Tuosto, L. CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters. Proc. Natl Acad. Sci. USA 101, 6098–6103 (2004).
Wang, D. et al. CD3/CD28 costimulation-induced NF-κB activation is mediated by recruitment of protein kinase C-Θ, Bcl10, and IκB kinase β to the immunological synapse through CARMA1. Mol. Cell. Biol. 24, 164–171 (2004).
Leadbetter, E. A. et al. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002).
Viglianti, G. A. et al. Activation of autoreactive B cells by CpG dsDNA. Immunity 19, 837–847 (2003).
Leadbetter, E. A., Rifkin, I. R. & Marshak-Rothstein, A. Toll-like receptors and activation of autoreactive B cells. Curr. Dir. Autoimmun. 6, 105–122 (2003).
Wright, S. D., Ramos, R. A., Tobias, P. S., Ulevitch, R. J. & Mathison, J. C. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249, 1431–1433 (1990).
Poltorak, A., Ricciardi-Castagnoli, P., Citterio, A. & Beutler, B. Physical contact between LPS and Tlr4 revealed by genetic complementation. Proc. Natl Acad. Sci. USA 97, 2163–2167 (2000).
Wang, P. Y. & Munford, R. S. CD14-dependent internalization and metabolism of extracellular phosphatidylinositol by monocytes. J. Biol. Chem. 274, 23235–23241 (1999).
Asch, A. S., Barnwell, J., Silverstein, R. L. & Nachman, R. L. Isolation of the thrombospondin membrane receptor 3. J. Clin. Invest. 79, 1054–1061 (1987).
Dawson, D. W. et al. CD36 mediates the in vitro inhibitory effects of thrombospondin-1 on endothelial cells. J. Cell Biol. 138, 707–717 (1997).
Endemann, G. et al. CD36 is a receptor for oxidized low density lipoprotein 2. J. Biol. Chem. 268, 11811–11816 (1993).
El Khoury, J. B. et al. CD36 mediates the innate host response to β-amyloid 1. J. Exp. Med. 197, 1657–1666 (2003).
Crawford, S. E. et al. Thrombospondin-1 is a major activator of TGF-β1 in vivo. Cell 93, 1159–1170 (1998).
Lewis, P. A. & Loomis, D. The formation of anti-sheep hemolytic amboceptor in the normal and tuberculous guinea pig. J. Exp. Med. 40, 503 (1924).
Freund, J. & McDermott, K. Sensitization to horse serum by means of adjuvants. Proc. Soc. Exp. Biol. Med. 49, 548–553 (1942).
Condie, R. M., Zak, S. J. & Good, R. A. Effect of meningococcal endotoxin on the immune response. Proc. Soc. Exp. Biol. Med. 90, 355–360 (1955).
Le Bon, A. et al. Type I interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo. Immunity 14, 461–470 (2001).
Le Bon, A. & Tough, D. F. Links between innate and adaptive immunity via type I interferon. Curr. Opin. Immunol. 14, 432–436 (2002).
Honda, K. et al. Selective contribution of IFN-α/β signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection Proc. Natl Acad. Sci. USA 100, 10872–10877 (2003).
Krieg, A. M. Antitumor applications of stimulating toll-like receptor 9 with CpG oligodeoxynucleotides. Curr. Oncol. Rep. 6, 88–95 (2004).
Maurer, T. et al. CpG-DNA aided cross-presentation of soluble antigens by dendritic cells. Eur. J. Immunol. 32, 2356–2364 (2002).
Heikenwalder, M. et al. Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nature Med. 10, 187–192 (2004).
O'Neill, L. A. Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases. Curr. Opin. Pharmacol. 3, 396–403 (2003).
Broide, D. & Raz, E. DNA-Based immunization for asthma. Int. Arch. Allergy Immunol. 118, 453–456 (1999).
Goldstein, D. R., Tesar, B. M., Akira, S. & Lakkis, F. G. Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection. J. Clin. Invest. 111, 1571–1578 (2003).
Bernard, G. R. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 344, 699–709 (2001).
Annane, D. et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. J. Am. Med. Assoc. 288, 862–871 (2002).
Smirnova, I. et al. Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility Proc. Natl Acad. Sci. USA 100, 6075–6080 (2003).
Hawn, T. R. et al. A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease. J. Exp. Med. 198, 1563–1572 (2003).
Kawata, T. et al. E5531, a synthetic non-toxic lipid A derivative blocks the immunobiological activities of lipopolysaccharide. Br. J. Pharmacol. 127, 853–862 (1999).
Bartfai, T. et al. A low molecular weight mimic of the Toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses. Proc. Natl Acad. Sci. USA 100, 7971–7976 (2003).
Suzuki, N. et al. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 416, 750–756 (2002).
Yamamoto, M. et al. Role of adapter TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301, 640–643 (2003).
Yamamoto, M. et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nature Immunol. 4, 1144–1150 (2003).
Jiang, Z. et al. Poly(I-C)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFκB and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3–TRAF6–TAK1–TAB2–PKR. J. Biol. Chem. 278, 16713–16719 (2003).
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Beutler, B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature 430, 257–263 (2004). https://doi.org/10.1038/nature02761
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DOI: https://doi.org/10.1038/nature02761
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