2. Academic Validation
  3. Oxysterols direct immune cell migration via EBI2

Oxysterols direct immune cell migration via EBI2

  • Nature. 2011 Jul 27;475(7357):524-7. doi: 10.1038/nature10280.
Sébastien Hannedouche 1,  Juan Zhang,  Tangsheng Yi,  Weijun Shen,  Deborah Nguyen,  João P Pereira,  Danilo Guerini,  Birgit U Baumgarten,  Silvio Roggo,  Ben Wen,  Richard Knochenmuss,  Sophie Noël,  Francois Gessier,  Lisa M Kelly,  Mirka Vanek,  Stephane Laurent,  Inga Preuss,  Charlotte Miault,  Isabelle Christen,  Ratna Karuna,  Wei Li,  Dong-In Koo,  Thomas Suply,  Christian Schmedt,  Eric C Peters,  Rocco Falchetto,  Andreas Katopodis,  Carsten Spanka,  Marie-Odile Roy,  Michel Detheux,  Yu Alice Chen,  Peter G Schultz,  Charles Y Cho,  Klaus Seuwen,  Jason G Cyster,  Andreas W Sailer
Affiliations

Affiliation

  • 1 Euroscreen S.A., 6041 Gosselies, Belgium.
PMID: 21796212 DOI: 10.1038/nature10280
Abstract

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. 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). 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.

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