IL36RN

Interleukin-36 receptor antagonist (IL-36Ra), a secreted cytokine of the IL-1 family that serves as the sole antagonist of the IL-36 signaling axis. Member of IL-36 subfamily which includes three pro-inflammatory agonists (IL-36α/β/γ) and this single antagonist. Encoded as 155-amino acid precursor that requires N-terminal proteolytic processing (removal of initiator Met and adjacent residues by neutrophil elastase) to achieve full antagonist activity - unprocessed form has drastically reduced receptor-binding capacity. Primary molecular function: competitive antagonist of IL-36 receptor (IL-36R/IL1RL2) - binds IL-36R with high affinity (Kd ~5-6 nM, much stronger than IL-36 agonists at 480-1800 nM) and slow dissociation rate, effectively blocking receptor occupancy. Critical mechanistic difference from agonists: IL-36Ra binding prevents recruitment of IL-1RAcP co-receptor, thereby blocking formation of functional signaling complex and preventing downstream MyD88-dependent activation of NF-κB and MAPK pathways. Structurally adopts β-trefoil fold characteristic of IL-1 family but lacks conventional signal peptide - secreted via unconventional pathways (likely microparticles/exosomes or during cell stress). Expressed in barrier tissues (skin keratinocytes, intestinal epithelium) and immune cells (monocytes, macrophages, dendritic cells); some cells constitutively express IL-36Ra to maintain basal antagonism preventing spontaneous inflammation. Essential role in immune homeostasis: loss-of-function mutations cause generalized pustular psoriasis (GPP/DITRA), a severe autoinflammatory skin disease with widespread sterile pustules and systemic inflammation, demonstrating that unopposed IL-36 signaling is life-threatening. Patients with processing-defective variant (p.V2F) that cannot be N-terminally cleaved have inactive IL-36Ra despite normal expression, proving proteolytic maturation is mandatory for function. Also implicated in other inflammatory conditions: rare IL36RN mutations found in severe Crohn's disease; IL-36Ra expressed in inflamed synovium in rheumatoid/psoriatic arthritis. Knockout mice show delayed wound healing due to excessive prolonged inflammation and neutrophil accumulation. IL-36Ra limits chemokine production (CXCL1, IL-8) and restrains Th17 responses. In 2022, FDA approved spesolimab (anti-IL-36R antibody) for GPP treatment, validating IL-36 pathway as therapeutic target and confirming IL-36Ra's natural protective role. Beyond immunity, potential context-dependent roles in cancer (may suppress pro-tumor inflammation in some settings). IL-38 (IL1F10) can also antagonize IL-36R but with more restricted activity. Overall, IL-36Ra is paradigmatic cytokine antagonist maintaining immune equilibrium at epithelial barriers by tightly blocking IL-36-driven inflammatory amplification.