The EBI2-oxysterol axis promotes the development of intestinal lymphoid structures and colitis

Adrian Wyss ,René Roth,Gérard Schmelczer,Andreas W Sailer,Marianne R Spalinger,Caroline Pot,Nathan Perkins,Florian Ruiz,Martin Hersberger,Oliver Pabst,Tina Raselli,Kirstin Atrott,Michael Scharl,Isabelle Frey-Wagner,Larissa Hering,Joachim C Mertens,Anja Moncsek,Glynis Klinke,Silvia Lang,Gerhard Rogler,Benjamin Misselwitz

doi:10.1038/s41385-019-0140-x

Abstract

The gene encoding for Epstein-Barr virus-induced G-protein-coupled receptor 2 (EBI2) is a risk gene for inflammatory bowel disease (IBD). Together with its oxysterol ligand 7α,25-dihydroxycholesterol, EBI2 mediates migration and differentiation of immune cells. However, the role of EBI2 in the colonic immune system remains insufficiently studied. We found increased mRNA expression of EBI2 and oxysterol-synthesizing enzymes (CH25H, CYP7B1) in the inflamed colon of patients with ulcerative colitis and mice with acute or chronic dextran sulfate sodium (DSS) colitis. Accordingly, we detected elevated levels of 25-hydroxylated oxysterols, including 7α,25-dihydroxycholesterol in mice with acute colonic inflammation. Knockout of EBI2 or CH25H did not affect severity of DSS colitis; however, inflammation was decreased in male EBI2−/− mice in the IL-10 colitis model. The colonic immune system comprises mucosal lymphoid structures, which accumulate upon chronic inflammation in IL-10-deficient mice and in chronic DSS colitis. However, EBI2−/− mice formed significantly less colonic lymphoid structures at baseline and showed defects in inflammation-induced accumulation of lymphoid structures. In summary, we report induction of the EBI2-7α,25-dihydroxycholesterol axis in colitis and a role of EBI2 for the accumulation of lymphoid tissue during homeostasis and inflammation. These data implicate the EBI2-7α,25-dihydroxycholesterol axis in IBD pathogenesis.

Highlights

Inflammatory bowel diseases (IBD), with the main forms Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory conditions of the human gut
Human intestinal lymphocytes express Epstein-Barr virus-induced G-protein-coupled receptor 2 (EBI2) To test for surface expression of EBI2 on intestinal immune cells, colon lamina propria mononuclear cells (LPMC) from patients undergoing intestinal surgery were analyzed by flow cytometry
Measurements of EBI2 and oxysterol-synthesizing enzymes in human and murine colon samples and oxysterol levels in mice. ii) EBI2 is required for efficient formation of solitary intestinal lymphoid tissue (SILT) in the mouse colon. iii) EBI2 is required for accumulation of lymphoid tissue in chronic mouse colitis. iv) EBI2 increases the severity of colitis in the IL-10 colitis model but not in acute or chronic dextran sulfate sodium (DSS) colitis

Summary

Introduction

Inflammatory bowel diseases (IBD), with the main forms Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory conditions of the human gut. The pathogenesis of IBD is incompletely understood, but genetic and environmental factors were shown to contribute to disease development and progression. Genome wide association studies (GWAS) have identified more than 240 genetic regions in the human genome affecting the risk for IBD.[1,2] The majority of IBD-specific single nucleotide polymorphisms (SNPs) confer an increased risk for both, CD and UC.[1] Genes identified by GWAS provide a framework for future scientific studies addressing IBD pathogenesis. Epstein-Barr virus-induced G-protein-coupled receptor 2 (EBI2, known as GPR183), is an IBD risk gene identified by GWAS.[1]

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