Chapter 13 : Toll-Like Receptors: Ligands and Signaling

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This chapter focuses on recent advances in one's understanding of the function of toll-like receptors (TLRs), particularly with regard to their ligands and signaling. Fibrinogen has been shown to induce the production of chemokines from macrophages through recognition by TLR4. Thus, TLR4 is presumably involved in several inflammatory responses by recognizing endogenous ligands even in the absence of infection. Therefore, more careful experiments are required before one can conclude that TLR4 recognizes these endogenous ligands. The signaling pathways via TLRs originate from the Toll/interleukin-1 receptor (TIR) domain. MyD88 harboring the TIR domain in the carboxy-terminal portion associates with the TIR domain of TLRs. MyD88-deficient mice showed impaired responses to the IL-1 family of cytokines, whose receptors have the cytoplasmic TIR domain. IFN-α has been shown to be induced in response to the activation of TLR7 as well as TLR4. In attempts to characterize the MyD88-independent signaling pathway, a second adaptor molecule containing the TIR domain was identified and designated TIR adaptor protein (TIRAP) or MyD88- adaptor-like. Initial in vitro studies suggested that TIRAP specifically associates with TLR4 and acts as an adaptor in the MyD88-independent signaling pathway. These studies further indicate that the TIR domain-containing molecules provide the specificity for individual TLR-mediated signaling pathways. Elucidation of the signaling pathway that is specific to each TLR will provide one with an important clue to understanding the molecular mechanisms by which innate immunity is activated and finally lead to the development of antigen-specific adaptive immunity.

Citation: Takeda K, Akira S. 2004. Toll-Like Receptors: Ligands and Signaling, p 257-270. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch13
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Image of FIGURE 1

TLRs and their ligands. TLR2 is essential in the recognition of microbial lipopeptides.TLR1 and TLR6 cooperate with TLR2 to discriminate subtle differences between triacyl and diacyl lipopeptides, respectively. TLR4 is the receptor for LPS. TLR9 is essential in CpG DNA recognition, whereas TLR3 is implicated in the recognition of viral dsRNA. TLR5 recognizes flagellin. Thus, the TLR family members recognize specific patterns of bacterial components.

Citation: Takeda K, Akira S. 2004. Toll-Like Receptors: Ligands and Signaling, p 257-270. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch13
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Image of FIGURE 2

The LPS receptor complex. The LPS receptor comprises several components. TLR4 is an essential receptor component for the signal transduction via the LPS receptor complex. MD-2 associates with the extracellular portion of TLR4 and is involved in the LPS recognition. LBP is a soluble molecule that binds to the lipid A portion of LPS. The LPS–LBP complex binds to CD14 and then this complex associates with TLR4. In B cells, additional components, RP105 and MD-1, are involved in the LPS recognition.

Citation: Takeda K, Akira S. 2004. Toll-Like Receptors: Ligands and Signaling, p 257-270. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch13
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Image of FIGURE 3

MyD88-dependent signaling pathway. A TIR domain-containing adaptor molecule, MyD88, associates with the cytoplasmic TIR domain of TLRs and recruits IRAKs to the receptor upon receptor activation. IRAKs then activate TRAF6, leading to the activation of MAP kinases and NF-κB. TIRAP, a second TIR domain-containing adaptor, is involved in the MyD88-dependent signaling pathway via TLR2 and TLR4.

Citation: Takeda K, Akira S. 2004. Toll-Like Receptors: Ligands and Signaling, p 257-270. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch13
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Image of FIGURE 4

MyD88-independent signaling pathway. In the TLR3- and TLR4-mediated signaling pathways, LPS-induced activation of IRF-3 is observed in MyD88-deficient mice, indicating the presence of a MyD88-independent pathway. It remains unclear how IRF-3 is activated. Recently, a TIR domain-containing adaptor, TRIF, was found to associate with IRF-3 and TLR3, indicating a possible role for TRIF in the MyD88-independent pathway.

Citation: Takeda K, Akira S. 2004. Toll-Like Receptors: Ligands and Signaling, p 257-270. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch13
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