NEMO Maintains Intestinal Homeostasis by Preventing Epithelial Cell Apoptosis and Necroptosis

The IKK/NF-κB signalling pathway regulates immune and inflammatory responses by inducing the expression of proinflammatory mediators, but also protects cells from cytokine-induced death. We showed previously that deletion of NEMO/IKKγ, the regulatory subunit of the IKK complex that is essential for activation of canonical NFkB signalling, in the intestinal epithelium of mice (NEMO^IEC-KO mice) caused the development of spontaneous chronic inflammatory colitis. Therefore, in contrast to the well-established proinflammatory function of the IKK/NF-κB pathway, inhibition of NEMO-dependent signalling in the intestinal epithelium triggered inflammation. Here we addressed the mechanisms by which NEMO knockout in IECs induces colitis. We show that colitis in NEMO^IEC-KO mice is dependent on the presence of the intestinal microbiota and is mediated by intestinal epithelial specific TNFR1 signalling. Furthermore we provide genetic evidence that IECs of NEMO^IEC-KO mice undergo cell death via both RIPK3-mediated necroptosis and FADD-dependent apoptosis. Inhibition of both apoptosis and necroptosis by combined knockout of FADD and RIPK3 protected NEMO^IEC-KO mice from intestinal epithelial cell death and inflammation. Therefore NEMO dependent signalling in the intestinal epithelium is essential to maintain intestinal homeostasis by preventing apoptosis and necroptosis.