학술논문
ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS–STING
Document Type
Article
Author
Aden, Konrad; Tran, Florian; Ito, Go; Sheibani-Tezerji, Raheleh; Lipinski, Simone; Kuiper, Jan W.; Tschurtschenthaler, Markus; Saveljeva, Svetlana; Bhattacharyya, Joya; Häsler, Robert; Bartsch, Kareen; Luzius, Anne; Jentzsch, Marlene; Falk-Paulsen, Maren; Stengel, Stephanie T.; Welz, Lina; Schwarzer, Robin; Rabe, Björn; Barchet, Winfried; Krautwald, Stefan; Hartmann, Gunther; Pasparakis, Manolis; Blumberg, Richard S.; Schreiber, Stefan; Kaser, Arthur; Rosenstiel, Philip
Source
The Journal of Experimental Medicine; November 2018, Vol. 215 Issue: 11 p2868-2886, 19p
Subject
Language
ISSN
00221007; 15409538
Abstract
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 Atg16l1ΔIEC 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 Atg16l1ΔIEC and Atg16l1ΔIEC/Xbp1ΔIEC 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 Atg16l1ΔIEC mice. Our data demonstrate an unexpected role of ATG16L1 in coordinating the outcome of IL-22 signaling in the intestinal epithelium.