IFN-gamma-Induced Intestinal Epithelial Cell-Type-Specific Programmed Cell Death: PANoptosis and Its Modulation in Crohn's Disease

Crohns disease (CD) is a chronic inflammatory bowel disease (IBD) and is considered a Th1-mediated disease, supported by the over-expression of interferon-gamma (IFN-{gamma}) in the intestinal lamina propria. To evaluate the response of intestinal epithelial cells (IECs) to IFN-{gamma}, we established small intestinal organoids (enteroids) derived from non-IBD controls and CD patients. IFN-{gamma} stimulated programmed cell death (PCD) of IECs in both control and CD enteroids in a dose-dependent manner. Pyroptosis, apoptosis and necroptosis were activated in enteroids, suggesting that PANoptosis was the main process of IFN-{gamma}-induced PCD in IECs. The response to IFN-{gamma} depends on the cell type of the IECs. IFN-{gamma} induced depletion of enterocytes with upregulation of PANoptosis-associated genes, while leading to expansion of goblet cells without significant change in PANoptosis-associated gene expression. Individual PCD inhibitors were insufficient to block IFN-{gamma}-induced cytotoxicity, whereas the selective JAK1 inhibitor (upadacitinib) effectively blocked IFN-{gamma}-induced cytotoxicity and PANoptosis. Furthermore, PANoptosis was significantly activated in surgically resected tissues and in publicly available single-cell RNA-sequencing datasets of intestinal tissues from patients with CD. In conclusion, IFN-{gamma} induces PANoptosis in enterocytes, which can be treated with a selective JAK1 inhibitor in patients with CD.