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J Exp Med. 2017 Feb;214(2):401-422. doi: 10.1084/jem.20160791. Epub 2017 Jan 12.

Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis.

Author information

1
Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK.
2
Institute for Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel, Germany.
3
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
4
Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
5
Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, 3015 CE Rotterdam, Netherlands.
6
Laboratory of Molecular and Cell Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan.
7
Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Kahoku, Ishikawa 920-0293, Japan.
8
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0QQ, England, UK.
9
Eastman Dental Institute, University College London, London WC1E 6BT, England, UK.
10
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 ak729@cam.ac.uk rblumberg@bwh.harvard.edu.
11
Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK ak729@cam.ac.uk rblumberg@bwh.harvard.edu.

Abstract

ATG16L1T300A, a major risk polymorphism in Crohn's disease (CD), causes impaired autophagy, but it has remained unclear how this predisposes to CD. In this study, we report that mice with Atg16l1 deletion in intestinal epithelial cells (IECs) spontaneously develop transmural ileitis phenocopying ileal CD in an age-dependent manner, driven by the endoplasmic reticulum (ER) stress sensor IRE1α. IRE1α accumulates in Paneth cells of Atg16l1ΔIEC mice, and humans homozygous for ATG16L1T300A exhibit a corresponding increase of IRE1α in intestinal epithelial crypts. In contrast to a protective role of the IRE1β isoform, hyperactivated IRE1α also drives a similar ileitis developing earlier in life in Atg16l1;Xbp1ΔIEC mice, in which ER stress is induced by deletion of the unfolded protein response transcription factor XBP1. The selective autophagy receptor optineurin interacts with IRE1α, and optineurin deficiency amplifies IRE1α levels during ER stress. Furthermore, although dysbiosis of the ileal microbiota is present in Atg16l1;Xbp1ΔIEC mice as predicted from impaired Paneth cell antimicrobial function, such structural alteration of the microbiota does not trigger ileitis but, rather, aggravates dextran sodium sulfate-induced colitis. Hence, we conclude that defective autophagy in IECs may predispose to CD ileitis via impaired clearance of IRE1α aggregates during ER stress at this site.

PMID:
28082357
PMCID:
PMC5294857
DOI:
10.1084/jem.20160791
[Indexed for MEDLINE]
Free PMC Article

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