Toll-like receptor signalling

Toll-like receptors (TLRs) have an extracellular region, which contains leucine-rich repeat motifs, and a cytoplasmic tail, which has a Toll/interleukin-1(IL-1) receptor (TIR) domain.Different TLRs recognize different surface and intracellular components of microorganisms.The interaction between a TLR and a microbial component triggers the activation of the innate immune system, as well as the development of acquired immunity.TLR-signalling pathways originate from the TIR domain, as a result of its recruitment of TIR-domain-containing adaptors — such as MyD88 (myeloid differentiation primary-response protein 88), TIRAP (TIR-domain-containing adaptor protein), TRIF (TIR-domain-containing adaptor protein inducing interferon-β) and TRAM (TRIF-related adaptor molecule).Signalling through each TLR requires MyD88 for the production of inflammatory cytokines. However, a MyD88-independent pathway exists, and following signalling through TLR3 or TLR4, it leads to the production of type I interferons.TRIF is essential for the MyD88-independent pathway of TLR3 and TLR4 signalling, as well as for the TLR4-mediated production of inflammatory cytokines.TRAM is involved specifically in the TLR4-mediated, MyD88-independent pathway, whereas TIRAP mediates the TLR2- and TLR4-mediated, MyD88-dependent pathway.The TLR-signalling pathways are negatively regulated by TLR-inducible molecules — such as IRAK-M (IL-1-receptor (IL-1R)-associated kinase M), SOCS1 (suppressor of cytokine signalling 1), MyD88s (MyD88 short), SIGIRR (single immunoglobulin IL-1R-related molecule) and ST2.