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
  • 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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