New Perspectives on Paracrine IL-18 Signaling in the Intestinal Epithelium

IL-18 is a member of the IL-1 family of cytokines, which is highly expressed in intestinal epithelial cells (IECs). Upon barrier breach, IL-18 is matured to its bioactive form as a result of inflammasome activation, released from the cell via Gasdermin D pores, and sensed by IL-18 receptor 1-positive (IL18R1⁺) immune cells to initiate an inflammatory response. In addition to this epithelial-out signaling network, we recently uncovered an epithelial-intrinsic IL-18 signaling pathway in the murine small intestine and identified enterochromaffin cells and revival stem cells (revSC) as IL18R1⁺ bearing IEC populations in the recovering crypt. Here, we discuss the mechanism, and physiological relevance, as well as some of the open questions presented by this discovery in relation to intestinal health and disease.