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

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 extraintestinal 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.

Diverse Immunoregulatory Roles of Oxysterols—The Oxidized Cholesterol Metabolites

“…The strongest evidence linking oxysterols to inflammatory colon disease is for 7α-25-HC, which is a ligand for the cell surface receptor GPR183. 7α-25-HC is found to be elevated in both the colon and livers of mice in colitis models [ 142 , 143 ]. 7α-25-HC is important in the formation of lymphoid structures in the colon in a GPR183-dependent manner [ 143 ].…”

“…7α-25-HC is found to be elevated in both the colon and livers of mice in colitis models [ 142 , 143 ]. 7α-25-HC is important in the formation of lymphoid structures in the colon in a GPR183-dependent manner [ 143 ]. One source of the 7α-25-HC are fibroblastic stromal cells that express high levels of Ch25h and Cyp7b1 [ 81 ].…”

“…One source of the 7α-25-HC are fibroblastic stromal cells that express high levels of Ch25h and Cyp7b1 [ 81 ]. The mechanism involves the recruitment the GPR183-expressing innate lymphocyte subset ILC3, an immune subset with important roles in gut immunology, and in doing so facilitates the formation of these gut lymphoid structures and contributes to colon inflammation [ 81 , 143 ]. Mice deficient for GPR183 expression or 7α-25-HC production show reduced formation of these colonic lymphoid structures [ 81 , 143 ].…”

“…The mechanism involves the recruitment the GPR183-expressing innate lymphocyte subset ILC3, an immune subset with important roles in gut immunology, and in doing so facilitates the formation of these gut lymphoid structures and contributes to colon inflammation [ 81 , 143 ]. Mice deficient for GPR183 expression or 7α-25-HC production show reduced formation of these colonic lymphoid structures [ 81 , 143 ]. Therefore, the 7α-25-HC/GPR183 migratory axis is an important factor in gut immune homeostasis and for inflammatory processes in the colon.…”

Tissue-resident lymphocytes: weaponized sentinels at barrier surfaces

“…This is in addition to the capacity for ILC2s to exit the bone marrow to replenish tissue pools following IL-33 62 or fungal aeroallergen challenge 63 . Similarly, ILC3s exhibit a constant influx and egress from the cryptopatch during inflammation, a circuitry driven by stromal cell oxysterol activation of the GPR183 receptor 64 – 66 . Collectively, these studies highlight that a highly orchestrated receptor expression pattern guides the recruitment and strategic positioning of innate cells in tissues and their deployment to distant sites when local perturbations occur.…”