IFN‐γ stimulates Paneth cell secretion through necroptosis mTORC1 dependent

Abstract Immune mediators affect multiple biological functions of intestinal epithelial cells (IECs) and, like Paneth and Paneth‐like cells, play an important role in intestinal epithelial homeostasis. IFN‐γ a prototypical proinflammatory cytokine disrupts intestinal epithelial homeostasis. However, the mechanism underlying the process remains unknown. In this study, using in vivo and in vitro models we demonstrate that IFN‐γ is spontaneously secreted in the small intestine. Furthermore, we observed that this cytokine stimulates mitochondrial activity, ROS production, and Paneth and Paneth‐like cell secretion. Paneth and Paneth‐like secretion downstream of IFN‐γ, as identified here, is mTORC1 and necroptosis‐dependent. Thus, our findings revealed that the pleiotropic function of IFN‐γ also includes the regulation of Paneth cell function in the homeostatic gut.