TLR signaling pathways

https://doi.org/10.1016/j.smim.2003.10.003Get rights and content

Abstract

Toll-like receptors (TLRs) have been established to play an essential role in the activation of innate immunity by recognizing specific patterns of microbial components. TLR signaling pathways arise from intracytoplasmic TIR domains, which are conserved among all TLRs. Recent accumulating evidence has demonstrated that TIR domain-containing adaptors, such as MyD88, TIRAP, and TRIF, modulate TLR signaling pathways. MyD88 is essential for the induction of inflammatory cytokines triggered by all TLRs. TIRAP is specifically involved in the MyD88-dependent pathway via TLR2 and TLR4, whereas TRIF is implicated in the TLR3- and TLR4-mediated MyD88-independent pathway. Thus, TIR domain-containing adaptors provide specificity of TLR signaling.

Introduction

Toll receptor was originally identified in Drosophila as an essential receptor for the establishment of the dorso-ventral pattern in developing embryos [1]. In 1996, Hoffmann and colleagues demonstrated that Toll-mutant flies were highly susceptible to fungal infection [2]. This study made us aware that the immune system, particularly the innate immune system, has a skilful means of detecting invasion by microorganisms. Subsequently, mammalian homologues of Toll receptor were identified one after another, and designated as Toll-like receptors (TLRs). Functional analysis of mammalian TLRs has revealed that they recognize specific patterns of microbial components that are conserved among pathogens, but are not found in mammals. In signaling pathways via TLRs, a common adaptor, MyD88, was first characterized as an essential component for the activation of innate immunity by all the TLRs. However, accumulating evidence indicates that individual TLRs exhibit specific responses. Furthermore, they have their own signaling molecules to manifest these specific responses. In this review, we will focus on the recent advances in our understanding of the mechanism of TLR-mediated signaling pathways.

Section snippets

Toll-like receptors

A mammalian homologue of Drosophila Toll receptor (now termed TLR4) was shown to induce the expression of genes involved in inflammatory responses [3]. In addition, a mutation in the Tlr4 gene was identified in mouse strains that were hyporesponsive to lipopolysaccharide [4]. Since then, Toll receptors in mammals have been a major focus in the immunology field. First, several proteins that are structurally similar to TLR4 were identified and named TLRs [5]. The TLR family now consists of 10

Signaling pathways via TLRs

The activation of TLR signaling pathways originates from the cytoplasmic TIR domains. A crucial role for the TIR domain was first revealed in the C3H/HeJ mouse strain, which had a point mutation that resulted in an amino acid change of the cytoplasmic proline residue at position 712 to histidine [4], [6]. This proline residue in the TIR domain is conserved among all TLRs, except for TLR3, and its substitution to histidine caused a dominant negative effect on TLR-mediated signaling [6], [7]. In

MyD88-dependent pathway

MyD88 possesses the TIR domain in the C-terminal portion, and a death domain in the N-terminal portion. MyD88 associates with the TIR domain of TLRs. Upon stimulation, MyD88 recruits IL-1 receptor-associated kinase (IRAK) to TLRs through interaction of the death domains of both molecules. IRAK is activated by phosphorylation and then associates with TRAF6, leading to the activation of two distinct signaling pathways, and finally to the activation of JNK and NF-κB (Fig. 2).

MyD88-independent pathway

As described above, MyD88 knockout mice did not show any production of inflammatory cytokines, such as TNF-α and IL-12, in response to any of the TLR ligands. Furthermore, activation of NF-κB and JNK in response to the TLR2, TLR7, and TLR9 ligands was not observed in MyD88 knockout mice. However, in the case of TLR4 stimulation, LPS-induced activation of NF-κB and JNK was observed with delayed kinetics, even in MyD88 knockout cells, although these cells did not produce any inflammatory

TIR domain-containing adaptors

During analysis of the MyD88-independent pathway, two TIR domain-containing adaptors, TIR domain-containing adaptor protein (TIRAP)/MyD88-adaptor-like (Mal) and TIR domain-containing adaptor inducing IFN-β (TRIF)/TIR domain-containing adaptor molecule (TICAM-1), were identified [45], [46], [47], [48]. Analysis of these two adaptors indicated that TIR domain-containing adaptors regulate the TLR-mediated signaling pathways by providing specificity for individual TLR signaling cascades (Fig. 3).

Future prospects

Since the discovery of TLRs in mammals, rapid progress has been made on our understanding of the molecular mechanisms of innate immunity. Individual TLRs recognize their specific microbial components and activate signaling pathways. The TLR signaling pathways also have their own cascades for exhibiting their specific responses, which are characterized by several TIR domain-containing adaptors. Elucidation of the physiological roles of these adaptors will provide important clues for

Acknowledgements

We thank M. Hashimoto for excellent secretarial assistance. This work was supported by grants from the Special Coordination Funds of the Ministry of Education, Culture, Sports, Science and Technology, and the Japan Research Foundation for Clinical Pharmacology.

References (53)

  • S.E. Doyle et al.

    IRF3 mediates a TLR3/TLR4-specific antiviral gene program

    Immunity

    (2002)
  • M. Sato et al.

    Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-α/β gene induction

    Immunity

    (2000)
  • L.H. Bin et al.

    TIRP: a novel TIR domain-containing adapter protein involved in Toll/interleukin-1 receptor signaling

    J. Biol. Chem.

    (2003)
  • R. Medzhitov et al.

    A human homologue of the Drosophila Toll protein signals activation of adaptive immunity

    Nature

    (1997)
  • A. Poltorak et al.

    Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutation in Tlr4 gene

    Science

    (1998)
  • F.L. Rock et al.

    A family of human receptors structurally related to Drosophila Toll

    Proc. Natl. Acad. Sci. U.S.A.

    (1998)
  • K. Hoshino et al.

    Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product

    J. Immunol.

    (1999)
  • D.M. Underhill et al.

    The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens

    Nature

    (1999)
  • S. Akira et al.

    Toll-like receptors: critical proteins linking innate and acquired immunity

    Nat. Immunol.

    (2001)
  • O. Takeuchi et al.

    Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signaling cascades

    Int. Immunol.

    (2000)
  • O. Takeuchi et al.

    Cutting edge: preferentially the R-stereoisomer of the Mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a Toll-like receptor 2- and MyD88-dependent signaling pathway

    J. Immunol.

    (2000)
  • H. Hacker et al.

    Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6

    J. Exp. Med.

    (2000)
  • H. Hemmi et al.

    Small antiviral compounds activate immune cells via TLR7 MyD88-dependent signalling pathway

    Nat. Immunol.

    (2002)
  • F. Hayashi et al.

    The innate immune response to bacterial flagellin is mediated by Toll-like receptor-5

    Nature

    (2001)
  • K. Burns et al.

    Inhibition of IL-1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4

    J. Exp. Med.

    (2003)
  • Z. Cao et al.

    Irak: a kinase associated with the interleukin-1 receptor

    Science

    (1996)
  • Cited by (1984)

    View all citing articles on Scopus
    View full text