Interleukin-1 receptor-associated kinase M (IRAK-M)

Interleukin-1 receptor-associated kinase M (IRAK-M), also known as IRAK3, is a member of the IRAK family of kinases that participate in Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways, pivotal to innate immunity. Structurally, IRAK-M possesses an N-terminal death domain, a central pseudokinase (kinase-like but catalytically inactive) domain, and a C-terminal domain with a TRAF6 interaction motif. While related to functional kinases IRAK-1 and IRAK-4, IRAK-M lacks key catalytic residues and is considered a pseudokinase. IRAK-M is primarily expressed in monocytes, macrophages, and lung epithelial cells, where it serves as a negative regulator of TLR and IL-1R signaling to prevent excessive inflammation, maintaining immune homeostasis and tolerance. Upon stimulation, IRAK-M impedes the dissociation of the MyD88/IRAK-4/IRAK-1 complex, inhibiting downstream NF-κB and MAPK activation and subsequent inflammatory gene transcription. Mice lacking IRAK-M show exaggerated inflammatory responses, and in humans, altered IRAK-M activity has been linked to sepsis, chronic inflammation, tumor progression, and immune tolerance. Therapeutically, while no approved drugs directly target IRAK-M, its modulation is of interest in diseases characterized by immune overactivation or immunosuppression. As a biomarker, its upregulation indicates suppressive innate immune states (e.g., endotoxin tolerance). However, targeting IRAK-M may introduce risks of exacerbated inflammatory disease or impaired infection control due to loss of negative feedback on immune signaling.

Other names

IRAK3IRAKMInterleukin-1 receptor-associated kinase 3

Negative regulation of TLR/IL-1R signaling cascade; acts by binding to myddosome components (MyD88, IRAK-1, IRAK-4) to inhibit downstream activation of NF-κB and MAPK pathways