Intestinal Epithelial Cell Autophagy Is Required to Protect against TNF-Induced Apoptosis during Chronic Colitis in Mice

Publication date: 14 February 2018
Source:Cell Host & Microbe, Volume 23, Issue 2
Author(s): Johanna Pott, Agnieszka Martyna Kabat, Kevin Joseph Maloy
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 (Atg16l1^VC) 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 Atg16l1^VC 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.

Graphical abstract

Teaser

Autophagy is genetically linked with inflammatory bowel disease. Using tissue-specific Atg16l1 knockout mice, Pott et al. demonstrate that autophagy within the intestinal epithelium maintains barrier integrity and limits inflammation by protecting the cells from TNF-induced apoptosis in a model of chronic colitis.


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