IL36RN encodes interleukin-36 receptor antagonist (IL-36Ra), a negative regulator of IL-36 signaling that functions as a competitive antagonist of proinflammatory IL-36 cytokines (IL-36α, IL-36β, IL-36γ) 1. IL-36Ra binds to the IL-36 receptor complex and prevents association with coreceptor IL1RAP, thereby suppressing NF-κB pathway activation and downstream inflammatory responses 2. This antagonist is particularly important at epithelial barrier sites including skin, where it regulates the balance between proinflammatory and anti-inflammatory IL-36 isoforms 1. IL36RN mutations are a major genetic cause of generalized pustular psoriasis (GPP) and other pustular phenotypes including palmoplantar pustulosis and acrodermatitis continua of Hallopeau 345. Null mutations causing complete loss of IL-36Ra protein expression are associated with severe GPP, while hypomorphic mutations result in decreased function and milder localized disease 2. The dysregulated IL-36 pathway resulting from IL36RN deficiency provides a molecular basis for targeted therapies; spesolimab, an IL-36 receptor antagonist monoclonal antibody, is the first disease-specific treatment approved for acute GPP flares 5. Understanding IL36RN function has expanded therapeutic potential beyond psoriasis to other inflammatory skin diseases and intestinal inflammation 6.