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

Aden K, Tran F, Ito G, Sheibani-Tezerji R, Lipinski S, Kuiper JW, Tschurtschenthaler M, Saveljeva S, Bhattacharyya J, Häsler R, Bartsch K, Luzius A, Jentzsch M, Falk-Paulsen M, Stengel ST, Welz L, Schwarzer R, Rabe B, Barchet W, Krautwald S, Hartmann G, Pasparakis M, Blumberg RS, Schreiber S, Kaser A, Rosenstiel P

J. Exp. Med. 2018 Nov;215(11):2868-2886

PMID: 30254094

Abstract

A coding variant of the inflammatory bowel disease (IBD) risk gene 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 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 and / 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 mice. Our data demonstrate an unexpected role of in coordinating the outcome of IL-22 signaling in the intestinal epithelium.

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