Regulation of interferon signaling in response to gut microbes by autophagy.

The cellular degradative pathway of autophagy prevents unrestrained inflammatory signaling by removing intracellular microbes, damaged organelles, and other factors that trigger immune reactions. Consistent with this function, a common variant of the autophagy gene is associated with susceptibility to inflammatory bowel disease (IBD), a disorder characterized by a chronic immune reaction directed against the gut microbiota. We recently contributed to our understanding of the link between autophagy and inflammatory signaling in the intestine by demonstrating that autophagy proteins including ATG16L1 are necessary in the epithelium to prevent a spontaneous type I interferon response to the gut microbiota. Enhanced innate immunity that occurs upon autophagy inhibition is protective in mouse models of infection by an enteric bacterial pathogen and acute epithelial injury. Although avoiding excess immune reactions towards the microbiota is necessary to prevent IBD, these observations indicate that autophagy hampers productive immunity at the intestinal epithelial barrier in certain contexts. Here, we discuss how this counterintuitive consequence of autophagy inhibition can be reconciled with the established beneficial role of the pathway.