A coding variant of the inflammatory bowel disease (IBD) risk gene ATG16L1 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 Atg16l1IEC intestinal organoids. IFN-I signals amplify epithelial TNF production downstream of IL-22 and contribute to necroptotic cell death. In vivo, IL-22 treatment in Atg16l1IEC and Atg16l1IEC/Xbp1IEC 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 Atg16l1IEC mice. Our data demonstrate an unexpected role of ATG16L1 in coordinating the outcome of IL-22 signaling in the intestinal epithelium. SOURCE: Robert Haesler (r.haesler@mucosa.de) - Functional Genomics Platform University Clinic of Schleswig Holstein

Pluto Bioinformatics

GSE119354: RNA-Seq as part of a study to investigate impact of Atg16l on Il22 signalling in the intestinal mucosa