Breaking bad: necroptosis in the pathogenesis of gastrointestinal diseases.

A delicate balance between programmed cell death and proliferation of intestinal epithelial cells (IEC) exists in the gut to maintain homeostasis. Homeostatic cell death programs such as anoikis and apoptosis ensure the replacement of dead epithelia without overt immune activation. In infectious and chronic inflammatory diseases of the gut, this balance is invariably disturbed by increased levels of pathologic cell death. Pathological forms of cell death such as necroptosis trigger immune activation barrier dysfunction, and perpetuation of inflammation. A leaky and inflamed gut can thus become a cause of persistent low-grade inflammation and cell death in other organs of the gastrointestinal (GI) tract, such as the liver and the pancreas. In this review, we focus on the advances in the molecular and cellular understanding of programmed necrosis (necroptosis) in tissues of the GI tract. In this review, we will first introduce the reader to the basic molecular aspects of the necroptosis machinery and discuss the pathways leading to necroptosis in the GI system. We then highlight the clinical significance of the preclinical findings and finally evaluate the different therapeutic approaches that attempt to target necroptosis against various GI diseases. Finally, we review the recent advances in understanding the biological functions of the molecules involved in necroptosis and the potential side effects that may occur due to their systemic inhibition. This review is intended to introduce the reader to the core concepts of pathological necroptotic cell death, the signaling pathways involved, its immuno-pathological implications, and its relevance to GI diseases. Further advances in our ability to control the extent of pathological necroptosis will provide better therapeutic opportunities against currently intractable GI and other diseases.

E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis.

Inflammatory bowel diseases present with elevated levels of intestinal epithelial cell (IEC) death, which compromises the gut barrier, activating immune cells and triggering more IEC death. The endogenous signals that prevent IEC death and break this vicious cycle, allowing resolution of intestinal inflammation, remain largely unknown. Here we show that prostaglandin E2 signalling via the E-type prostanoid receptor 4 (EP4) on IECs represses epithelial necroptosis and induces resolution of colitis. We found that EP4 expression correlates with an improved IBD outcome and that EP4 activation induces a transcriptional signature consistent with resolution of intestinal inflammation. We further show that dysregulated necroptosis prevents resolution, and EP4 agonism suppresses necroptosis in human and mouse IECs. Mechanistically, EP4 signalling on IECs converges on receptor-interacting protein kinase 1 to suppress tumour necrosis factor-induced activation and membrane translocation of the necroptosis effector mixed-lineage kinase domain-like pseudokinase. In summary, our study indicates that EP4 promotes the resolution of colitis by suppressing IEC necroptosis.