IRAKM

IRAKM, or Interleukin-1 receptor-associated kinase M, is a member of the interleukin-1 receptor-associated kinase family that functions as a negative regulator of Toll-like receptor and interleukin-1 receptor signaling. In humans, the gene is commonly designated IRAK3, and the protein is also referred to as IRAK-M or IRAKM.

IRAK-M is mainly expressed in monocytes, macrophages and dendritic cells. It contains a kinase-like domain but is catalytically inactive, functioning primarily as a scaffold to limit signaling rather than to propagate it. Upon TLR or IL-1 receptor engagement, IRAK-M is induced and acts to blunt downstream signaling.

Mechanistically, IRAK-M interferes with the MyD88-dependent signaling axis by preventing the proper assembly and activation of the IRAK-1/IRAK-4 and TRAF6 complex, thereby reducing NF-κB and MAPK activation and the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-12.

Physiologically, IRAK-M contributes to endotoxin tolerance and helps balance immune responses to prevent excessive inflammation. Altered expression has been observed in sepsis and some chronic inflammatory conditions; in experimental systems, loss of IRAK-M enhances inflammation, while overexpression dampens responses, highlighting its potential as a therapeutic target.