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Oxysterols direct immune cell migration through EBI2

Hannedouche, Sébastien and Zhang, Juan and Yi, Tangsheng and Shen, Weijun and Nguyen, Deborah and Pereira, Joao P. and Guerini, Danilo and Baumgarten, Birgit and Roggo, Silvio and Wen, Ben and Knochenmuss, Richard and Noel, Sophie and Gessier, Francois and Kelly, Lisa M. and Vanek, Miroslava and Laurent, Stephane and Preuss, Inga and Miault, Charlotte and Christen, Isabelle and Karuna, Ratnaningrum and Li, Wei and Koo, Dong-In and Suply, Thomas and Schmedt, Christian and Peters, Eric and Falchetto, Rocco Angelo and Katopodis, Andreas and Spanka, Carsten and Roy, Marie-Odile and Detheux, Michel and Chen, Yu and Schultz, Peter and Cho, Charles and Seuwen, Klaus and Cyster, Jason G. and Sailer, Andreas (2011) Oxysterols direct immune cell migration through EBI2. Nature, 475 (7357). pp. 524-527. ISSN 0028-0836

Abstract

Epstein-Barr virus (EBV)-induced gene 2 (EBI2, aka GPR183) is a G protein-coupled receptor that is required for humoral immune responses and polymorphisms in the receptor have been associated with inflammatory autoimmune diseases1-3. The natural ligand for EBI2 has been unknown. Here we describe identification of 7, 25-dihydroxycholesterol (5-cholesten-3, 7, 25-triol; 7, 25-OHC) as a potent and selective agonist of EBI2. Functional activation of EBI2 by 7, 25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high affinity radioligand binding. Furthermore we find that 7, 25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A key enzyme required for the generation of 7, 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 bioactivity in vivo and suggests that the EBI2 oxysterol signaling pathway plays an important role in the adaptive immune response.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: EBI2, oxysterols, CH25H
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4169

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