The IL-18 receptor is expressed on murine small-intestinal enterochromaffin cells and executes a recovery program upon injury

Upon injury, epithelial-derived IL-18 is released and induces an inflammatory response in underlying IL18R1⁺ lamina propria cells. Notably, <i>Il18r1</i> is also predicted to be expressed and functional in intestinal epithelial cells (IECs), since epithelial IL18R1 deficiency contributes to worsened outcomes upon inflammatory challenge. However, the nature of <i>Il18r1⁺</i> IECs, and their subsequent role in epithelial-intrinsic IL-18 signaling is poorly characterized. Here, we show that, in the murine small intestine, the IL-18 receptor is expressed by rare IECs that we identified to be a subset of enterochromaffin cells (ECC). While these cells are the major producers of serotonin in the intestine, we found no evidence that IL-18 regulated serotonin metabolism or release. Rather, upon radiation-induced injury, <i>Il18r1⁺</i> cells appeared in the crypt base and took on a revival stem cell (revSC) program, marked by mixed expression of YAP/TAZ and enteroendocrine genes signatures. Functionally, irradiated <i>Il18^-/-</i> mice display reduced epithelial proliferation and altered differentiation in the small intestine, characterized by increased Paneth cells (PC) and elevated <i>Wnt3</i> levels, which was partially recapitulated in <i>Il18^-/-</i> ileal organoids. In sum, we identified an <i>Il18r1</i>⁺ population in the epithelium and revealed a role for IEC-intrinsic IL-18 signaling during injury.