Aden, Konrad ORCID: 0000-0003-3482-7316, Tran, Florian, Ito, Go, Sheibani-Tezerji, Raheleh, Lipinski, Simone, Kuiper, Jan W., Tschurtschenthaler, Markus ORCID: 0000-0002-0060-4790, Saveljeva, Svetlana, Bhattacharyya, Joya ORCID: 0000-0003-1745-4167, Haesler, Robert, Bartsch, Kareen, Luzius, Anne, Jentzsch, Marlene, Falk-Paulsen, Maren, Stengel, Stephanie T., Welz, Lina, Schwarzer, Robin, Rabe, Bjoern, Barchet, Winfried ORCID: 0000-0002-6745-6606, Krautwald, Stefan ORCID: 0000-0001-7768-2132, Hartmann, Gunther ORCID: 0000-0003-1021-2018, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Blumberg, Richard S., Schreiber, Stefan, Kaser, Arthur and Rosenstiel, Philip ORCID: 0000-0002-9692-8828 (2018). ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS-STING. J. Exp. Med., 215 (11). S. 2868 - 2887. NEW YORK: ROCKEFELLER UNIV PRESS. ISSN 1540-9538

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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 STI NG-dependent type I interferon (IFN-I) signaling, which is augmented in Atg16l1(Delta IEC) 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 Atg16l1(Delta IEC) and Atg16l1(Delta IEC)/Xbp1(Delta IEC) 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 Atg16l1(Delta IEC) mice. Our data demonstrate an unexpected role of ATG16L1 in coordinating the outcome of IL-22 signaling in the intestinal epithelium.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Aden, KonradUNSPECIFIEDorcid.org/0000-0003-3482-7316UNSPECIFIED
Tran, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ito, GoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sheibani-Tezerji, RahelehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lipinski, SimoneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuiper, Jan W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tschurtschenthaler, MarkusUNSPECIFIEDorcid.org/0000-0002-0060-4790UNSPECIFIED
Saveljeva, SvetlanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bhattacharyya, JoyaUNSPECIFIEDorcid.org/0000-0003-1745-4167UNSPECIFIED
Haesler, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartsch, KareenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luzius, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jentzsch, MarleneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Falk-Paulsen, MarenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stengel, Stephanie T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Welz, LinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwarzer, RobinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rabe, BjoernUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barchet, WinfriedUNSPECIFIEDorcid.org/0000-0002-6745-6606UNSPECIFIED
Krautwald, StefanUNSPECIFIEDorcid.org/0000-0001-7768-2132UNSPECIFIED
Hartmann, GuntherUNSPECIFIEDorcid.org/0000-0003-1021-2018UNSPECIFIED
Pasparakis, ManolisUNSPECIFIEDorcid.org/0000-0002-9870-0966UNSPECIFIED
Blumberg, Richard S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schreiber, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaser, ArthurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenstiel, PhilipUNSPECIFIEDorcid.org/0000-0002-9692-8828UNSPECIFIED
URN: urn:nbn:de:hbz:38-167072
DOI: 10.1084/jem.20171029
Journal or Publication Title: J. Exp. Med.
Volume: 215
Number: 11
Page Range: S. 2868 - 2887
Date: 2018
Publisher: ROCKEFELLER UNIV PRESS
Place of Publication: NEW YORK
ISSN: 1540-9538
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
INFLAMMATORY-BOWEL-DISEASE; INTERFERON-STIMULATED GENES; INNATE LYMPHOID-CELLS; CROHNS-DISEASE; ER STRESS; I IFN; SUSCEPTIBILITY LOCI; PANETH CELLS; DNA-DAMAGE; STEM-CELLSMultiple languages
Immunology; Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/16707

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