ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS–STING

Abstract

A coding variant of the inflammatory bowel disease (IBD) risk gene <i>ATG16L1</i> has been associated with defective autophagy and deregulation of endoplasmic reticulum (ER) function. IL-22 is a barrier protective cytokine by inducing regeneration and antimicrobial responses in the intestinal mucosa. We show that ATG16L1 critically orchestrates IL-22 signaling in the intestinal epithelium. IL-22 stimulation physiologically leads to transient ER stress and subsequent activation of STING-dependent type I interferon (IFN-I) signaling, which is augmented in <i>Atg16l1</i> ^ΔIEC intestinal organoids. IFN-I signals amplify epithelial TNF production downstream of IL-22 and contribute to necroptotic cell death. In vivo<i>,</i> IL-22 treatment in <i>Atg16l1</i> ^ΔIEC and <i>Atg16l1</i> ^ΔIEC/<i>Xbp1</i> ^ΔIEC mice potentiates endogenous ileal inflammation and causes widespread necroptotic epithelial cell death. Therapeutic blockade of IFN-I signaling ameliorates IL-22-induced ileal inflammation in <i>Atg16l1</i> ^ΔIEC mice. Our data demonstrate an unexpected role of <i>ATG16L1</i> in coordinating the outcome of IL-22 signaling in the intestinal epithelium.