PL-1 The IL-1 receptor/Toll-like receptor superfamily: 10 Years of progress

The IL-1R/TLR superfamily was first defined in detail 10 years ago. Since then, there has been remarkable progress in our understanding of both branches of the superfamily. Ligands have been described for most receptors. Within the IL-1R subfamily, notable examples include IL33 for ST2 and IL-1F6 for IL-1Rrp2. The role of TLRs in the sensing of microbial products has led to a renaissance of interest in innate immune mechanisms. For investigators interested in signal transduction, the area has proved very fruitful in terms of the discovery of new signalling pathways and processes. MyD88 is the universal adapter for the superfamily and its central role in inflammation, host defence and even in certain cancers, has been confirmed from studies in knockout mice. We now have a good understanding of the major components activated by TLRs, notably the TIR domain- containing adapters that initiate signalling following recruitment to TIR domains within the TLRs themselves, the IRAK family of protein kinases that are then recruited, and a series of ubiquitination and phosphorylation reactions that ultimately lead to the activation of transcription factors such as NF-κB and IRF family members. The structural basis for signalling is still poorly understood however, and we have no appreciation of the kinetics involved in the pathways. Additional components and regulatory cross-talk from multiple signals also continue to be discovered. Genetic variation in signalling components such as in IRAK4, Mal and Unc93b however highlight the importance of these pathways in human health and disease. I will discuss our recent findings of a novel component in TLR4 signalling, what genetic variation in Mal tells us about the evolution of host defence to pathogens and also the molecular basis to how Mal signals, and the emerging role of miRNAs as key regulators of TLR signalling events.