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The EBI2-oxysterol axis promotes the development of intestinal lymphoid structures and colitis
Mucosal Immunology ( IF 8 ) Pub Date : 2019-02-11 , DOI: 10.1038/s41385-019-0140-x
Annika Wyss 1 , Tina Raselli 1 , Nathan Perkins 2 , Florian Ruiz 3 , Gérard Schmelczer 1 , Glynis Klinke 2, 4 , Anja Moncsek 1 , René Roth 1 , Marianne R Spalinger 1 , Larissa Hering 1 , Kirstin Atrott 1 , Silvia Lang 1 , Isabelle Frey-Wagner 1 , Joachim C Mertens 1 , Michael Scharl 1 , Andreas W Sailer 5 , Oliver Pabst 6 , Martin Hersberger 2 , Caroline Pot 3 , Gerhard Rogler 1 , Benjamin Misselwitz 1, 7
Affiliation  

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.



中文翻译:

EBI2-氧甾醇轴促进肠道淋巴结构和结肠炎的发展

编码 EB 病毒诱导的 G 蛋白偶联受体 2 (EBI2) 的基因是炎症性肠病 (IBD) 的风险基因。EBI2 与其氧固醇配体 7α,25-二羟基胆固醇一起介导免疫细胞的迁移和分化。然而,EBI2 在结肠免疫系统中的作用仍未得到充分研究。我们发现溃疡性结肠炎患者和急性或慢性葡聚糖硫酸钠 (DSS) 结肠炎小鼠的发炎结肠中 EBI2 和氧固醇合成酶(CH25H、CYP7B1)的 mRNA 表达增加。因此,我们在患有急性结肠炎症的小鼠中检测到 25-羟基化氧固醇水平升高,包括 7α,25-二羟基胆固醇。EBI2 或 CH25H 的敲除不影响 DSS 结肠炎的严重程度;然而,男性 EBI2 的炎症减少了−/− IL-10 结肠炎模型中的小鼠。结肠免疫系统包含粘膜淋巴结构,其在 IL-10 缺陷小鼠和慢性 DSS 结肠炎中的慢性炎症中积累。然而,EBI2 -/-小鼠在基线时形成明显较少的结肠淋巴结构,并显示炎症诱导的淋巴结构积聚存在缺陷。总之,我们报告了结肠炎中 EBI2-7α,25-二羟基胆固醇轴的诱导以及 EBI2 在稳态和炎症过程中对淋巴组织积聚的作用。这些数据表明 IBD 发病机制中的 EBI2-7α,25-二羟基胆固醇轴。

更新日期:2019-07-05
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