Defective ATG16L1-mediated Removal of IRE1α Drives Crohn's Disease-like Ileitis

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2017 Jan 14

PMID 28082357

Citations 99

Authors

Markus Tschurtschenthaler

Timon E Adolph

Jonathan W Ashcroft

Lukas Niederreiter

Richa Bharti

Svetlana Saveljeva

Joya Bhattacharyya

Magdalena B Flak

David Q Shih

Gwenny M Fuhler

Miles Parkes

Kenji Kohno

Takao Iwawaki

C Janneke van der Woude

Heather P Harding

Andrew M Smith

Maikel P Peppelenbosch

Stephan R Targan

David Ron

Philip Rosenstiel

Richard S Blumberg

Arthur Kaser

Affiliations

Soon will be listed here.

Abstract

ATG16L1, 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 Atg16l1 mice, and humans homozygous for ATG16L1 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;Xbp1 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;Xbp1 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.

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