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

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

Published:2018-09-25 Issue:11 Volume:215 Page:2868-2886
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Aden Konrad¹²,Tran Florian¹²^ORCID,Ito Go¹³,Sheibani-Tezerji Raheleh¹,Lipinski Simone¹^ORCID,Kuiper Jan W.¹,Tschurtschenthaler Markus⁴⁵^ORCID,Saveljeva Svetlana⁵,Bhattacharyya Joya⁵^ORCID,Häsler Robert¹,Bartsch Kareen⁶,Luzius Anne¹,Jentzsch Marlene¹,Falk-Paulsen Maren¹,Stengel Stephanie T.¹,Welz Lina¹,Schwarzer Robin⁷,Rabe Björn⁶,Barchet Winfried⁸,Krautwald Stefan⁹^ORCID,Hartmann Gunther⁸,Pasparakis Manolis⁷,Blumberg Richard S.¹⁰^ORCID,Schreiber Stefan¹²,Kaser Arthur⁵^ORCID,Rosenstiel Philip¹^ORCID

Affiliation:

1. Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

2. Department of Internal Medicine I., Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

3. Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan

4. Department of Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany

5. Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge, England, UK

6. Institute of Biochemistry, Kiel University, Kiel, Germany

7. Institute for Genetics, CECAD, University of Cologne, Cologne, Germany

8. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany

9. Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

10. Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA

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.

Funder

DFG

Wellcome Trust

ERC FP7

Cambridge Biomedical Research Centre

National Institutes of Health

Harvard Digestive Diseases Center

EU H2020

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy