Inflammasome activation in intestinal epithelial cells drives cell extrusion via prostaglandin E receptor 4 (Ptger4) signaling 3295

Abstract Description The intestinal epithelium is a critical barrier site for immune tolerance and host protection. Intestinal epithelial cells (IECs) play a crucial role in homeostasis and the initiation of immune responses. Cell extrusion is required for homeostasis in the gastrointestinal tract and is essential for defense against invading pathogens, e.g., Shigella. Aberrant epithelial cell extrusion is commonly observed during infection, inflammatory bowel disease, and colorectal cancer. Cell extrusion involves both cell-intrinsic and cell-extrinsic mechanisms, but the pathways remain ill-defined. The inflammasome, a multiprotein complex formed after the recognition of intracellular infection or danger signals, notably, leads to cell extrusion and eicosanoid release in IECs. We hypothesized that eicosanoids act as a signal for rapid extrusion following inflammasome activation. We triggered extrusion via activating the NAIP/NLRC4 inflammasome in murine intestinal organoids. Inhibition of both leukotrienes and prostaglandins simultaneously was required to block cell extrusion in organoids derived from the small intestine. In contrast, inhibition of prostaglandins alone, specifically inhibiting Ptger4, blocked extrusion in organoids derived from the colon. This study establishes a role for eicosanoid signaling in cell extrusion and will lead to better understanding of how the small intestine and colon respond differently to inflammatory signals. Funding Sources Supported by the Howard Hughes Medical Institutue Hanna H. Gray Fellows Program Topic Categories Mucosal and Regional Immunology (MUC)