Innate immunity and Toll-like receptors

Excerpt

A recently described family of receptors, called the Toll-like receptors (TLRs), may help explain what triggers the production of inflammatory mediators such as tumour necrosis factor and chemokines in diseases such as rheumatoid arthritis. TLRs recognize microbial products and trigger signalling pathways, which culminate in enhanced expression of immune and inflammatory genes. They are emerging as key players in the pathogenesis of infectious and inflammatory diseases. TLRs are defined by the presence of leucine-rich repeats and a signalling domain, which contains the Toll/IL-1 receptor (TIR) domain. An important finding is that the cystolic domain of the receptor for the cytokine IL-1 is similar to TLRs and that they signal in a similar way. Ten TLRs exist in humans and the best characterized are TLR4, which senses lipopolysaccharide from Gram-negative bacteria, and TLR3, which senses viral RNA. Signalling by each TLR is initiated by the receptor TIR domain and recruits via homotypic adapter proteins that contain TIR domains. Five such adapters have been discovered to date including MyD88, Mal (also known as TIRAP), Trif, Tram, and SARM. Signals activated include the transcription factor NF-κB and mitogen-activated protein kinases, which lead to induction of gene expression. Differences are emerging between TLRs in terms of which adapter is recruited by which TLR. This may lead to specificities in TLR signalling, with pathways being triggered that are specific for the elimination of the invading microbe. …