Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1016/j.chom.2017.12.017

Type

Journal article

Journal

Cell Host Microbe

Publication Date

14/02/2018

Volume

23

Pages

191 - 202.e4

Keywords

Crohn’s disease, mucosal immunology, ulcerative colitis, Animals, Apoptosis, Autophagy, Carrier Proteins, Cell Line, Citrobacter rodentium, Colitis, Goblet Cells, HEK293 Cells, Helicobacter hepaticus, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells, Paneth Cells, Tumor Necrosis Factor-alpha