Toll-Like Receptors: Ligands and Signaling

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.