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Oxysterols direct immune cell migration via EBI2

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Overview

related to degree

  • Koo, Dong-In, Ph.D. in Chemical Biology, Scripps Research 2006 - 2011

authors

  • Hannedouche, S.
  • Zhang, J.
  • Yi, T. S.
  • Shen, W. J.
  • Nguyen, D.
  • Pereira, J. P.
  • Guerini, D.
  • Baumgarten, B. U.
  • Roggo, S.
  • Wen, B.
  • Knochenmuss, R.
  • Noel, S.
  • Gessier, F.
  • Kelly, L. M.
  • Vanek, M.
  • Laurent, S.
  • Preuss, I.
  • Miault, C.
  • Christen, I.
  • Karuna, R.
  • Li, W.
  • Koo, Dong-In
  • Suply, T.
  • Schmedt, C.
  • Peters, E. C.
  • Falchetto, R.
  • Katopodis, A.
  • Spanka, C.
  • Roy, M. O.
  • Detheux, M.
  • Chen, Y. A.
  • Schultz, Peter
  • Cho, C. Y.
  • Seuwen, K.
  • Cyster, J. G.
  • Sailer, A. W.

publication date

  • July 2011

journal

  • Nature  Journal

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.

subject areas

  • Animals
  • Antibody Formation
  • B-Lymphocytes
  • Cell Line
  • Cell Movement
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Hydroxycholesterols
  • Liver
  • Mice
  • Mice, Knockout
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Sheep
  • T-Lymphocytes
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Identity

PubMed Central ID

  • PMC4297623

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature10280

PubMed ID

  • 21796212
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Additional Document Info

start page

  • 524

end page

  • 527

volume

  • 475

issue

  • 7357

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