Oxysterols direct immune cell migration via EBI2

Autor: Tangsheng Yi, Andreas W. Sailer, Birgit Baumgarten, Miroslava Vanek, Deborah Nguyen, Sébastien Hannedouche, Richard Knochenmuss, Marie-Odile Roy, Inga Preuss, Jason G. Cyster, Charlotte Miault, Yu Chen, João Pereira, Isabelle Christen, Weijun Shen, Silvio Roggo, Peter G. Schultz, Wei Li, Danilo Guerini, Sophie Noël, Lisa M. Kelly, Christian Schmedt, Eric C. Peters, Ratnaningrum Karuna, Thomas Suply, Dong-In Koo, Stephane Laurent, Michel Detheux, Rocco Falchetto, Carsten Spanka, Ben Wen, Andreas Katopodis, François Gessier, Charles Y. Cho, Klaus Seuwen, Juan Zhang
Rok vydání: 2011
Předmět:
Zdroj: Nature. 475:524-527
ISSN: 1476-4687
0028-0836
DOI: 10.1038/nature10280
Popis: The EBI2 receptor (Epstein–Barr virus-induced gene 2, also known as GPR183) was recently shown to be linked to autoimmune disease, and is a critical regulator of the humoral immune response. It is a G-protein-coupled receptor, and its natural ligand has been unknown. Two groups now bring an end to the 'orphan' status of this receptor with identification of specific oxysterols as its natural ligands. The most potent ligand and activator is 7a,25-dihydroxycholesterol, and the EBI2–oxysterol signalling pathway has an important role in the adaptive immune response. 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 diseases1,2,3. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,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 7α,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.
Databáze: OpenAIRE
Externí odkaz: