Interleukin-17A Promotes Parietal Cell Atrophy by Inducing Apoptosis

Abstract

Background & AimsAtrophic 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.MethodsA 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.ResultsIncreased 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.ConclusionsThese data identify IL-17A as a cytokine that promotes parietal cell apoptosis during atrophic gastritis, a precursor lesion for gastric cancer.

Interferon‐γ directly induces gastric epithelial cell death and is required for progression to metaplasia

“…This is a critical observation, as IFN‐γ regulates many cellular behaviors and it was, prior to these studies, entirely plausible that the effects of IFN‐γ on gastric epithelium could be an indirect effect caused by downstream products of IFN‐γ signaling. Another feature of our study is that we show that atrophy and metaplasia in TxA23 mice, which eventually progress to marked cancer‐like dysplasia , depend nearly entirely on IFN‐γ, as TxA23 × Ifng −/− mice have inflammation but minimal other pathology, even at advanced age (5–7 months) for this model. We specifically determine that it is IFN‐γ within the supernatants from draining‐lymphocytes of wild‐type mice that is elevated in TxA23 mice and lost in Ifng −/− mice, with other cytokines not being significantly affected.…”

“…The finding that the predominant cytokine produced during both Helicobacter infection and autoimmune gastritis is capable of directly inducing epithelial cell death should advance our understanding of the pathogenesis of inflammation-induced gastric carcinogenesis. We have previously shown that another major component of the inflammatory milieu, IL-17A, can directly induce parietal cell atrophy via apoptosis [8]. It should be noted that data from both that study and this current one indicate that IFN-γ is roughly 100 times more concentrated and 10 times more potent at inducing cell death compared with IL-17A alone, and it is reasonable to hypothesize that there is a strong potential for synergy between these two arms of the immune response given that they have little overlap in their signaling pathways.…”

“…Changes in TxA23 mice that are similar to the progression to human cancer include atrophy, metaplasia, and, in some mice, lesions that resemble dysplasia in humans [14,23]. These histological changes are accompanied by increased abundance of important cytokines, chiefly IFN-γ and, to a lesser degree, IL-17A [8]. As previously reported, by 4 months TxA23 mice exhibited diffuse chronic inflammation and oxyntic atrophy, accompanied by mucous neck cell hyperplasia, SPEM, and occasional dysplasia-like lesions.…”

“…To determine the role that IFN-γ plays in promoting parietal cell atrophy, we used a TCR transgenic mouse model of chronic atrophic gastritis induced by CD4 + T cells that are autoreactive against the H + /K + -ATPase expressed by parietal cells. This model, referred to as TxA23, mimics many aspects of atrophic gastritis and gastric metaplasia in human patients including chronic inflammation and anti-parietal cell autoantibodies; infiltration of numerous IFN-γ-producing cells into the gastric mucosa; and the development of parietal cell atrophy, mucous neck cell hyperplasia, SPEM, and eventually gastric intraepithelial neoplasms [8,14,23]. In the present study, we observed IFN-γ receptor expression on gastric epithelial cells and used three-dimensional gastric corpus organoid cultures to show that IFN-γ directly induces organoid degeneration in a receptor-dependent manner.…”

“…The cause(s) of parietal cell atrophy have not been fully described and may include autoantibodies, inflammatory cytokines, Sonic hedgehog signaling, and/or other inducers of cell death (e.g. FAS-FASL) [8][9][10][11]. A better understanding of how chronic immune responses regulate mucosal lesion progression is needed to better identify those at risk of developing gastric cancer in the context of gastritis.In both H. pylori infection and autoimmune gastritis, type 1 immune responses characterized by Th1 CD4 + T cells and the production of interferon-γ (IFN-γ)…”