The IL-36 cytokine family: From barrier immunity to therapeutic target in inflammatory diseases

The interleukin-36 (IL-36) cytokine family is an important regulator of inflammatory responses at epithelial barrier surfaces, with particularly prominent roles in skin immunity and inflammatory disease. As members of the IL-1 superfamily, IL-36 cytokines include three agonists (IL-36α, IL-36β, and IL-36γ) and two antagonists (IL-36Ra and IL-38), which signal through a shared heterodimeric receptor complex to activate MyD88-dependent pathways, including NF-κB and MAPK, and induce pro-inflammatory cytokines, chemokines, and antimicrobial peptides. A defining feature of IL-36 biology is its dependence on proteolytic activation, whereby neutrophil- and pathogen-derived proteases convert low-activity precursors into highly active cytokines, enabling rapid amplification of inflammation and linking epithelial stress to neutrophil recruitment. The clinical relevance of IL-36 signaling was established by the identification of loss-of-function mutations in IL3 6RN, encoding IL-36Ra, in generalized pustular psoriasis (GPP), a severe and potentially life-threatening neutrophilic dermatosis. These discoveries validated IL-36R as a therapeutic target and culminated in regulatory approval of IL-36R blockade for the treatment of GPP flares. Beyond GPP, accumulating evidence implicates IL-36 in inflammatory processes across multiple organ systems. This review summarizes IL-36 molecular biology, receptor trafficking and signaling, and protease-dependent activation, and discusses roles in barrier immunity and host defense. We also synthesize evidence for pathogenic contributions of IL-36 across inflammatory skin diseases and extra-cutaneous disorders, and highlight emerging therapeutic strategies, biomarkers of response, and future clinical directions.