IL1RL2 is a cell-surface receptor for interleukin-36 cytokines (IL36A, IL36B, and IL36G) that associates with the coreceptor IL1RAP to activate NF-κB and MAPK signaling pathways involved in inflammatory responses. The IL-36 signaling system functions at epithelial barriers to mediate local inflammatory responses analogous to the IL-1 system, with particular involvement in skin inflammation through induction of the IL-23/IL-17/IL-22 pathway [UniProt annotation]. Recent evidence demonstrates IL1RL2's protective role in inflammatory diseases: genetically determined IL1RL2 levels show a protective association with ankylosing spondylitis (OR = 0.70, P = 3.22 × 10-4), suggesting potential therapeutic benefit from IL1RL2 enhancement 1. IL-36 receptor signaling participates in gut immunity with context-dependent pathogenic and protective roles in inflammatory bowel disease, as IL-36 ligands are overexpressed in both murine colitis models and human IBD patients 2. IL1RAP co-receptor expression patterns correlate with disease phenotypes, being elevated in severe neutrophilic and mixed granulocytic asthma alongside IL-33-activated gene signatures 3. These findings position IL1RL2/IL-36 signaling as a regulatory node in epithelial and mucosal immunity with bidirectional roles in inflammatory disease pathogenesis.