Oxysterols direct immune cell migration via EBI2

被引：381

作者：

Hannedouche, Sebastien ^{[2
]}

Zhang, Juan ^{[1
]}

Yi, Tangsheng ^{[3
,4
]}

Shen, Weijun ^{[5
,6
]}

Nguyen, Deborah ^{[5
]}

Pereira, Joao P. ^{[3
,4
]}

Guerini, Danilo ^{[1
]}

Baumgarten, Birgit U. ^{[1
]}

Roggo, Silvio ^{[1
]}

Wen, Ben ^{[5
]}

Knochenmuss, Richard ^{[1
]}

Noel, Sophie ^{[2
]}

Gessier, Francois ^{[1
]}

Kelly, Lisa M. ^{[3
,4
]}

Vanek, Mirka ^{[1
]}

Laurent, Stephane ^{[1
]}

Preuss, Inga ^{[1
]}

Miault, Charlotte ^{[1
]}

Christen, Isabelle ^{[1
]}

Karuna, Ratna ^{[1
]}

Li, Wei ^{[5
]}

Koo, Dong-In ^{[6
]}

Suply, Thomas ^{[1
]}

Schmedt, Christian ^{[5
]}

Peters, Eric C. ^{[5
]}

Falchetto, Rocco ^{[1
]}

Katopodis, Andreas ^{[1
]}

Spanka, Carsten ^{[1
]}

Roy, Marie-Odile ^{[2
]}

Detheux, Michel ^{[2
]}

Chen, Yu Alice ^{[5
]}

Schultz, Peter G. ^{[5
]}

Cho, Charles Y. ^{[5
]}

Seuwen, Klaus ^{[1
]}

Cyster, Jason G. ^{[3
,4
]}

Sailer, Andreas W. ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, CH-4056 Basel, Switzerland

[2] Euroscreen SA, B-6041 Gosselies, Belgium

[3] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA

[4] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA

[5] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

[6] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA

来源：

NATURE | 2011年 / 475卷 / 7357期

关键词：

DENDRITIC CELLS; CHOLESTEROL; EXPRESSION; MACROPHAGES; ENZYMES;

D O I：

10.1038/nature10280

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases(1-3). The natural ligand for EBI2 has been unknown. Here we describe the identification of 7 alpha,25-dihydroxycholesterol (also called 7 alpha,25-OHC or 5-cholesten-3 beta,7 alpha,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7 alpha,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7 alpha,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7 alpha,25-OHC is cholesterol 25-hydroxylase (CH25H)(4). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.

引用

页码：524 / 527

页数：4

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