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

Chronic inflammation of the gastric mucosa, often caused by autoimmune gastritis and/or infection with Helicobacter pylori, can lead to atrophy of acid-secreting parietal cells with metaplasia of remaining cells. The histological pattern marks a critical step in the progression from chronic gastritis to gastric cancer, yet underlying mechanism(s) of inflammation-induced cell death of gastric epithelial cells are poorly understood. We investigated direct effects of a type 1 cytokine associated with autoimmunity and infection, interferon-gamma (IFN-gamma), on gastric epithelial cells. IFN-gamma was applied to three-dimensional organoid cultures of gastric epithelial cells derived from gastric corpus gland (gastroids) of control and IFN-gamma receptor-deficient mice. Gastroids were also treated with supernatants from activated immune cells isolated from a mouse model of autoimmune-mediated atrophic gastritis (TxA23) with and without IFN-gamma expression. Finally, histopathological analysis of atrophy and metaplasia severity was performed in TxA23 mice and compared to TxA23 x Ifng(-/-) mice. Gastric epithelial cells in gastroid cultures expressed IFN-gamma receptor in the basolateral membrane, and gastroids died when treated with IFN-gamma in an IFN-gamma receptor-dependent manner. Supernatants from immune cells containing high levels of IFN-gamma were highly toxic to gastroids, and toxicity was tempered when IFN-gamma was either neutralized using a monoclonal antibody or when supernatants from Ifng(-/-) mouse immune cells were used. Finally, TxA23 x Ifng(-/-) mice showed near-complete abrogation of pre-cancerous histopathological atrophy and metaplasia versus IFN-gamma-sufficient controls. We identify IFN-gamma as a critical promoter of parietal cell atrophy with metaplasia during the progression of gastritis to gastric atrophy and metaplasia. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.