Intestinal epithelial cell autophagy is required to protect against TNF-induced apoptosis during chronic colitis in mice

Pott, J., Kabat, A. M. and Maloy, K. J. (2018) Intestinal epithelial cell autophagy is required to protect against TNF-induced apoptosis during chronic colitis in mice. Cell Host and Microbe, 23(2), 191-202.e4. (doi: 10.1016/j.chom.2017.12.017) (PMID:29358084)

[img]
Preview
Text
198288.pdf - Accepted Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.

1MB

Abstract

Genome-wide association studies have linked polymorphisms in the autophagy gene ATG16L1 with susceptibility to inflammatory bowel disease (IBD). However, the cell-type-specific effects of autophagy on the regulation of chronic intestinal inflammation have not been investigated. Here, we assessed the effect of myeloid-specific or intestinal epithelial cell (IEC)-specific deletion of Atg16l1 on chronic colitis triggered by the intestinal opportunistic pathogen Helicobacter hepaticus in mice. Although Atg16l1 deficiency in myeloid cells had little effect on disease, mice selectively lacking Atg16l1 in IECs (Atg16l1VC) developed severely exacerbated pathology, accompanied by elevated pro-inflammatory cytokine secretion and increased IEC apoptosis. Using ex vivo IEC organoids, we demonstrate that autophagy intrinsically controls TNF-induced apoptosis and in vivo blockade of TNF attenuated the exacerbated pathology in Atg16l1VC mice. These findings suggest that the IBD susceptibility gene ATG16L1 and the process of autophagy within the epithelium control inflammation-induced apoptosis and barrier integrity to limit chronic intestinal inflammation.

Item Type:Articles
Additional Information:Imaging was performed on Micron instruments funded by the Wellcome Trust Strategic Award (107457). J.P. was supported by an EMBO long-term fellowship (ALTF 1530-2011). K.J.M. and J.P. received funding from the MRC (MR/K011898/1 and MR/N02379X/1). K.J.M. received funding from the Wellcome Trust (102972). A.M.K. was supported by the Wellcome Trust Graduate Student Scholarship 097112.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Maloy, Professor Kevin
Authors: Pott, J., Kabat, A. M., and Maloy, K. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Cell Host and Microbe
Publisher:Elsevier
ISSN:1931-3128
ISSN (Online):1934-6069
Published Online:18 January 2018
Copyright Holders:Copyright © 2017 Elsevier Inc.
First Published:First published in Cell Host and Microbe 23(2):191-202.e4
Publisher Policy:Reproduced in accordance with the publisher copyright policy

University Staff: Request a correction | Enlighten Editors: Update this record