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.

Additional Metadata
Persistent URL dx.doi.org/10.1084/jem.20160791, hdl.handle.net/1765/97884
Journal The Journal of Experimental Medicine
Grant This work was funded by the European Commission 7th Framework Programme; grant id erc/260961 - XBP1 and Endoplasmic Reticulum Stress in Mucosal Homeostasis (MUCOSAL ER STRESS), This work was funded by the European Commission 7th Framework Programme; grant id erc/648889 - Identifying microbiotal triggers of inflammatory bowel disease through the lens of the immune system (IMMUNOBIOME)
Citation
Tschurtschenthaler, M. (Markus), Adolph, T.E. (Timon E.), Ashcroft, J.W. (Jonathan W.), Niederreiter, L. (Lukas), Bharti, R. (Richa), Saveljeva, S. (Svetlana), … Kaser, A. (2017). Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis. The Journal of Experimental Medicine, 214(2), 401–422. doi:10.1084/jem.20160791