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. 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 TNFα. Chronic overexpression of TNFα 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 TNFα-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 TNFα receptor I (TNFRI) in the villus tip rapidly after TNFα injection and concurrent with elevated levels of intracellular TNFα and rapid shed of 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 any increase in proliferative cell number or division rate within the crypt. Immunological changes in the chronic setting suggest a repair response to cell damage that re-establishes the epithelial barrier but fails to recover the villus tip. A better understanding of the intestinal epithelial response to inflammatory processes will help define early pathogenic events and 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: 09 Apr 2019 13:57
      URI: https://ueaeprints.uea.ac.uk/id/eprint/69149
      DOI: 10.1038/s41419-018-1275-5

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