IFN-γ is a direct driver of crypt hyperplasia in celiac disease
Jorunn Stamnaes, Daniel Stray, M. Fleur du Pré, Louise F. Risnes, Alisa E. Dewan, Jakeer Shaik, Maria Stensland, Knut E.A. Lundin, Ludvig M. Sollid
Jorunn Stamnaes, Daniel Stray, M. Fleur du Pré, Louise F. Risnes, Alisa E. Dewan, Jakeer Shaik, Maria Stensland, Knut E.A. Lundin, Ludvig M. Sollid
View: Text | PDF
Research Article Gastroenterology Immunology Inflammation

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

Abstract

Crypt hyperplasia is a key feature of celiac disease (CeD) and several other small intestinal inflammatory conditions. Analysis of the gut epithelial crypt zone by mass spectrometry–based tissue proteomics revealed a strong IFN-γ signal in active CeD. 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 WT mice administered IFN-γ. In mice with conditional KO of the IFN-γ receptor in gut epithelial cells, these signature morphological and proteomic changes were not induced with IFN-γ administration. IFN-γ was thus a driver of crypt hyperplasia in CeD by acting directly on crypt epithelial cells. The results are relevant to other enteropathies with involvement of IFN-γ.

Authors

Jorunn Stamnaes, Daniel Stray, M. Fleur du Pré, Louise F. Risnes, Alisa E. Dewan, Jakeer Shaik, Maria Stensland, Knut E.A. Lundin, Ludvig M. Sollid

×

Figure 5

Small intestinal tissue remodeling induced by IFN-γ in mice with targeted deletion of Ifngr1 in IECs.

Options: View larger image (or click on image) Download as PowerPoint
Small intestinal tissue remodeling induced by IFN-γ in mice with targete...
(A) Schematic depiction of the IFN-γ injection regime for mice with deletion of Ifngr1 (Ifngr1IEC−/−; KO) in IECs and the corresponding littermate controls (WT). (B and C) Measurement of the Vh/Cd ratio and epithelial cell migration speed based on EdU staining. For IFNx6 WT mice, the EdU migration front had reached the villi tips. (D) Crypt proteome analysis revealed the separation of samples along PC1 according to Ifngr1 status and IFN-γ injection. Each data point reflects 1 mouse. (E and F) Expression of proteins mapped to the indicated pathways. Each data point represents 1 protein and shows the median z-scored expression level per group. **P < 0.01 and ****P < 0.0001, by Mann-Whitney U test with Benjamin-Hochberg correction for multiple testing. (G and H) Tile plots of z-scored expression of proteins from pathways (G) upregulated in UCeD (Figure 2D; n = 21 mouse orthologs) and (H) downregulated in UCeD (Figure 2E; n = 30 mouse orthologs). (I and J) Expression (z-scored) of selected proteins involved in ketone body synthesis (I) and FASN involved in de novo lipid synthesis (J). Each data point reflects 1 mouse.