Much has been learned in the past few years about how the innate immune system functions. Dysregulation of innate immunity is thought to contribute to the pathogenesis of diseases such as Crohn's disease and inflammatory bowel disease, but the mechanisms by which innate immunity is regulated are not well understood. Now, Richard Flavell's group have shown that interleukin-1 (IL-1)-receptor-associated kinase M (IRAK-M) is a negative regulator of Toll-like receptor (TLR) signalling.

TLR-mediated recognition of pathogen-associated molecular patterns (PAMPs) on microorganisms leads to the activation of innate immunity. After ligand engagement, the adaptor protein MYD88 is recruited to the TLR. On recruitment to the signalling complex by MYD88, IRAK is phosphorylated, which allows it to dissociate from the complex and bind to downstream molecules such as TRAF6. This leads to the activation of various downstream effectors. The authors generated IRAK-M-knockout mice to investigate the role of IRAK-M — the expression of which is restricted to macrophages and monocytes — in TLR signalling.

IRAK-M-deficient macrophages produced more cytokines (IL-12 p40, IL-6 and TNF) than wildtype macrophages in response to stimulation with various PAMPs. Similarly, infection of the IRAK-M−/− macrophages with live or dead Gram-negative and Gram-positive bacteria led to the enhanced production of cytokines compared with wildtype cells. IRAK-M−/− mice were orally infected with Salmonella typhimurium and the effect of the IRAK-M deficiency on intestinal inflammation was examined. A greater number of enlarged Peyer's patches (PPs) was observed in the deficient mice, and the PPs had severe inflammatory infiltrates compared with wildtype mice.

Next, the authors investigated the effects of IRAK-M deficiency on TLR signalling pathways. TLR engagement on IRAK-M−/− macrophages led to more rapid phosphorylation of IκBα — a member of the NF-κB family — and a faster and more extensive phosphorylation of JNK, p38 and ERK1/2, which indicates that IRAK-M might negatively regulate these pathways.

So, how does IRAK-M function as a negative regulator? On the basis of a series of co-immunoprecipitation experiments, the authors suggest that, rather than inhibiting the association of IRAK with TRAF6, IRAK-M inhibits the dissociation of IRAK from the TLR signalling complex, and so prevents it from activating downstream mediators.