IFNγ contributes to the development of gastric epithelial cell metaplasia in Huntingtin interacting protein 1 related (Hip1r)-deficient mice

Huntingtin interacting protein 1 related (Hip1r) is an F-actin- and clathrin-binding protein involved in vesicular trafficking that is crucial for parietal cell function and epithelial cell homeostasis in the stomach. Gastric parietal cells in Hip1r-deficient mice are lost by apoptotic cell death, which leads to a progressive epithelial cell derangement, including glandular hypertrophy, zymogenic cell loss and expansion of a metaplastic mucous cell lineage known as spasmolytic polypeptide-expressing metaplasia (SPEM). The epithelial cell changes are associated with infiltration of inflammatory cells. As inflammatory mediators, such as IFN gamma, have been shown to contribute to the development of the gastric epithelial cell metaplasia after Helicobacter infection, we tested whether IFN gamma played a role in the spontaneous progressive epithelial metaplasia observed in Hip1r-deficient mice. Hip1r-deficient mice were crossed with IFN gamma-deficient mice and single- and double-mutant mice were analyzed at 3 and 12 months of age. Histopathology scoring showed that loss of IFN gamma tempered the spontaneous development of metaplastic lesions in Hip1r-deficient mice. Loss of IFN gamma was observed to abrogate the glandular hypertrophy evident in Hip1r mutant stomach, although increased epithelial cell proliferation and elevated gastrin levels were not affected by the presence or absence of this pro-inflammatory cytokine. An analysis of cell lineage markers in the double-mutant mice demonstrated that IFN gamma specifically affected the development of metaplastic mucous cells in the neck region, whereas the parietal cell, surface mucous cell and zymogenic cell alterations remained similar to the histopathology in the Hip1r mutant. Morphometric analysis showed that IFN gamma was required for the mucous cell hypertrophy and hyperplasia observed in Hip1r-deficient mice. Together, these findings demonstrate that IFN gamma is critical for the development of the gastric epithelial cell metaplasia that results from parietal cell atrophy in the Hip1r-deficient mice. Laboratory Investigation (2012) 92, 1045-1057; doi:10.1038/labinvest.2012.73; published online 23 April 2012