Interleukin-36 receptor (IL-36R) (IL-36R)

The Interleukin-36 receptor (IL-36R), also known as IL1RL2, is a heterodimeric receptor complex consisting of the ligand-binding subunit IL-1 receptor-like 2 and the co-receptor IL-1 receptor accessory protein (IL-1RAcP), belonging to the immunoglobulin-like family of IL-1 receptors. It binds proinflammatory agonists IL-36α, IL-36β, and IL-36γ, which are expressed primarily in barrier tissues such as skin, lung, and gut epithelial cells, while IL-36Ra acts as an antagonist by preventing co-receptor recruitment. Upon ligand binding, IL-36R activates intracellular signaling via Toll/IL-1 receptor (TIR) domains, recruiting MyD88, IRAKs, and TRAF6 to trigger NF-κB and MAPK pathways, leading to production of inflammatory cytokines like TNF-α, IL-6, and IL-8, and promoting immune cell infiltration. IL-36 cytokines require proteolytic processing by neutrophil proteases (e.g., cathepsin G, elastase) or cathepsin S for full activation, amplifying responses at epithelial barriers during infection or injury. Dysregulated IL-36R signaling drives pathogenesis in inflammatory skin diseases like psoriasis and contributes to fibrosis in organs such as kidney, lung, and intestine by linking inflammation to profibrotic processes via IL-23/IL-17 axis and TGF-β production. No approved drugs directly target IL-36R, but its role in chronic inflammation positions it as a potential therapeutic target, with challenges including managing hyperactivation feedback loops.

Other names

IL1RL2Interleukin-1 receptor-like 2IL-36 receptor