Innate immunity and Toll-like receptors
- LAJ O'Neill1
© BioMed Central Ltd 2004
Published: 13 September 2004
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.
Manipulation of proteins with TIR domains presents a number of opportunities for enhancing host defence or disease resistance, or strategies to limit inflammation. In the context of chronic inflammatory diseases, roles for TLRs in the pathogenesis of inflammation are emerging in conditions such as rheumatoid arthritis and systemic lupus erythematosus. Examples include the expression and action of TLRs in synoviocytes and a role for TLR9 in the production of rheumatoid factor from autore-active B cells. Since TLRs are likely to be key drivers of TNF production, limiting their actions may have clinical benefit in inflammatory diseases. Additionally, since signals like NF-κB and p38 mitogen-activated protein kinase are activated by TLRs, inhibiting these processes will limit the effect of TLRs. Recent evidence, that certain receptor signals activated by TLRs may have an inflammatory rather than an immune role, raises the possibility of limiting the proinflammatory effects of TLRs without affecting roles in host defence. Furthermore, certain members of the TLR family (SIGIRR and ST2) may in fact be inhibitory receptors, and several negative signals generated during TLR action have been identified. As information on TLRs accumulates, more opportunities will present themselves for drug development.