Interferon-γ is a direct driver of crypt hyperplasia in celiac disease

Crypt hyperplasia is a key feature of celiac disease and several other small intestinal inflammatory conditions. Analysis of the gut epithelial crypt zone by mass spectrometry-based tissue proteomics revealed a strong interferon-γ (IFN-γ) signal in active celiac disease. This signal, hallmarked by increased expression of MHC molecules, was paralleled by diminished expression of proteins associated with fatty acid metabolism. Crypt hyperplasia and the same proteomic changes were observed in wild type mice administered IFN-γ. In mice with conditional knockout of the IFN-γ receptor in gut epithelial cells these signature morphological and proteomic changes were not induced on IFN-γ administration. IFN-γ is thus a driver of crypt hyperplasia in celiac disease by acting directly on crypt epithelial cells. The results are relevant to other enteropathies with involvement of IFN-γ.