Interleukin-17A Promotes Parietal Cell Atrophy by Inducing Apoptosis

Kevin A Bockerstett, Luciana H Osaki, Christine P Petersen, Catherine W Cai, Chun Fung Wong, Thanh-Long M Nguyen, Eric L Ford, Daniel F Hoft, Jason C Mills, James R Goldenring, Richard J DiPaolo
Cellular and Molecular Gastroenterology and Hepatology 2018, 5 (4): 678-690.e1

Background & Aims: Atrophic gastritis caused by chronic inflammation in the gastric mucosa leads to the loss of gastric glandular cells, including acid-secreting parietal cells. Parietal cell atrophy in a setting of chronic inflammation induces spasmolytic polypeptide expressing metaplasia, a critical step in gastric carcinogenesis. However, the mechanisms by which inflammation causes parietal cell atrophy and spasmolytic polypeptide expressing metaplasia are not well defined. We investigated the role of interleukin-17A (IL-17A) in causing parietal cell atrophy.

Methods: A mouse model of autoimmune atrophic gastritis was used to examine IL-17A production during early and late stages of disease. Organoids derived from corpus glands were used to determine the direct effects of IL-17A on gastric epithelial cells. Immunofluorescent staining was used to examine IL-17A receptors and the direct effect of signaling on parietal cells. Mice were infected with an IL-17A-producing adenovirus to determine the effects of IL-17A on parietal cells in vivo. Finally, IL-17A neutralizing antibodies were administered to mice with active atrophic gastritis to evaluate the effects on parietal cell atrophy and metaplasia.

Results: Increased IL-17A correlated with disease severity in mice with chronic atrophic gastritis. IL-17A caused caspase-dependent gastric organoid degeneration, which could not be rescued with a necroptosis inhibitor. Parietal cells expressed IL-17A receptors and IL-17A treatment induced apoptosis in parietal cells. Overexpressing IL-17A in vivo induced caspase-3 activation and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining in parietal cells. Finally, IL-17A neutralizing antibody decreased parietal cell atrophy and metaplasia in mice with chronic atrophic gastritis.

Conclusions: These data identify IL-17A as a cytokine that promotes parietal cell apoptosis during atrophic gastritis, a precursor lesion for gastric cancer.

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