Elevated apoptosis impairs epithelial cell turnover and shortens villi in TNF-driven intestinal inflammation

Parker, Aimée, Vaux, Laura, Patterson, Angela, Modasia, Amisha, Muraro, Danial, Fletcher, Alexander, Byrne, Helen, Maini, Phillip, Watson, Alastair and Pin, Carmen (2019) Elevated apoptosis impairs epithelial cell turnover and shortens villi in TNF-driven intestinal inflammation. Cell Death & Disease, 10 (2). ISSN 2041-4889

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Abstract

The intestinal epithelial monolayer, at the boundary between microbes and the host immune system, plays an important role in the development of inflammatory bowel disease (IBD), particularly as a target and producer of pro-inflammatory TNF. Chronic overexpression of TNF leads to IBD-like pathology over time, but the mechanisms driving early pathogenesis events are not clear. We studied the epithelial response to inflammation by combining mathematical models with in vivo experimental models resembling acute and chronic TNF-mediated injury. We found significant villus atrophy with increased epithelial cell death along the crypt-villus axis, most dramatically at the villus tips, in both acute and chronic inflammation. In the acute model, we observed overexpression of TNF receptor I in the villus tip rapidly after TNF injection and concurrent with elevated levels of intracellular TNF and rapid shedding at the tip. In the chronic model, sustained villus atrophy was accompanied by a reduction in absolute epithelial cell turnover. Mathematical modelling demonstrated that increased cell apoptosis on the villus body explains the reduction in epithelial cell turnover along the crypt-villus axis observed in chronic inflammation. Cell destruction in the villus was not accompanied by changes in proliferative cell number or division rate within the crypt. Epithelial morphology and immunological changes in the chronic setting suggest a repair response to cell damage although the villus length is not recovered. A better understanding of how this state is further destabilised and results in clinical pathology resembling IBD will help identify suitable pathways for therapeutic intervention.

Item Type: Article
Uncontrolled Keywords: apoptosis,intestine,tnf
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 03 Dec 2018 16:31
Last Modified: 21 May 2020 00:09
URI: https://ueaeprints.uea.ac.uk/id/eprint/69149
DOI: 10.1038/s41419-018-1275-5

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