TLR signaling pathways
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.
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