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Oxysterols direct B-cell migration through EBI2

Naturevolume 475, pages519–523 (2011)Cite this article

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Abstract

EBI2 (also called GPR183) is an orphan G-protein-coupled receptor that is highly expressed in spleen and upregulated upon Epstein–Barr-virus infection1. Recent studies indicated that this receptor controls follicular B-cell migration and T-cell-dependent antibody production2,3,4,5,6. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol metabolism7,8,9. The biological effects of oxysterols have largely been credited to the activation of nuclear hormone receptors10,11. Here we isolate oxysterols from porcine spleen extracts and show that they are endogenous ligands for EBI2. The most potent ligand and activator is 7α,25-dihydroxycholesterol (OHC), with a dissociation constant of 450 pM for EBI2.In vitro, 7α,25-OHC stimulated the migration of EBI2-expressing mouse B and T cells with half-maximum effective concentration values around 500 pM, but had no effect on EBI2-deficient cells.In vivo, EBI2-deficient B cells or normal B cells desensitized by 7α,25-OHC pre-treatment showed reduced homing to follicular areas of the spleen. Blocking the synthesis of 7α,25-OHCin vivo with clotrimazole, a CYP7B1 inhibitor, reduced the content of 7α,25-OHC in the mouse spleen and promoted the migration of adoptively transferred pre-activated B cells to the T/B boundary (the boundary between the T-zone and B-zone in the spleen follicle), mimicking the phenotype of pre-activated B cells from EBI2-deficient mice. Our results show an unexpected causal link between EBI2, an orphan G-protein-coupled receptor controlling B-cell migration, and the known immunological effects of certain oxysterols, thus uncovering a previously unknown role for this class of molecules.

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Figure 1:Identification and pharmacological characterization of oxysterols as ligands for EBI2.
Figure 2:Regulation of EBI ligand synthesis in mouse spleen.
Figure 3:7α,25-OHC stimulates B-cell and T-cell migration.

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References

  1. Birkenbach, M., Josefsen, K., Yalamanchili, R., Lenoir, G. & Kieff, E. Epstein-Barr virus-induced genes: first lymphocyte-specific G protein-coupled peptide receptors.J. Virol.67, 2209–2220 (1993)

    CAS PubMed PubMed Central  Google Scholar 

  2. Pereira, J. P., Kelly, L. M., Xu, Y. & Cyster, J. G. EBI2 mediates B cell segregation between the outer and centre follicle.Nature460, 1122–1126 (2009)

    Article ADS CAS  Google Scholar 

  3. Pereira, J. P., Kelly, L. M. & Cyster, J. G. Finding the right niche: B-cell migration in the early phases of T-dependent antibody responses.Int. Immunol.22, 413–419 (2010)

    Article CAS  Google Scholar 

  4. Gatto, D., Paus, D., Basten, A., Mackay, C. R. & Brink, R. Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses.Immunity31, 259–269 (2009)

    Article CAS  Google Scholar 

  5. Goodnow, C. C., Vinuesa, C. G., Randall, K. L., Mackay, F. & Brink, R. Control systems and decision making for antibody production.Nature Immunol.11, 681–688 (2010)

    Article CAS  Google Scholar 

  6. Chan, T. D. et al.In vivo control of B-cell survival and antigen-specific B-cell responses.Immunol. Rev.237, 90–103 (2010)

    Article CAS  Google Scholar 

  7. Schroepfer, G. J., Jr Oxysterols: modulators of cholesterol metabolism and other processes.Physiol. Rev.80, 361–554 (2000)

    Article CAS  Google Scholar 

  8. Björkhem, I. & Diczfalusy, U. Oxysterols: friends, foes, or just fellow passengers?Arterioscler. Thromb. Vasc. Biol.22, 734–742 (2002)

    Article  Google Scholar 

  9. Zhao, C. & Dahlman-Wright, K. Liver X receptor in cholesterol metabolism.J. Endocrinol.204, 233–240 (2010)

    Article CAS  Google Scholar 

  10. Willy, P. J. et al. LXR, a nuclear receptor that defines a distinct retinoid response pathway.Genes Dev.9, 1033–1045 (1995)

    Article CAS  Google Scholar 

  11. Jin, L. et al. Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORγ.Mol. Endocrinol.24, 923–929 (2010)

    Article CAS  Google Scholar 

  12. Russell, D. W. Oxysterol biosynthetic enzymes.Biochim. Biophys. Acta1529, 126–135 (2000)

    Article CAS  Google Scholar 

  13. Smith, L. L. Cholesterol autoxidation 1981–1986.Chem. Phys. Lipids44, 87–125 (1987)

    Article CAS  Google Scholar 

  14. Rose, K. A. et al. Cyp7b, a novel brain cytochrome P450, catalyzes the synthesis of neurosteroids 7α-hydroxy dehydroepiandrosterone and 7α-hydroxy pregnenolone.Proc. Natl Acad. Sci. USA94, 4925–4930 (1997)

    Article ADS CAS  Google Scholar 

  15. Paila, Y. D. & Chattopadhyay, A. Membrane cholesterol in the function and organization of G-protein coupled receptors.Subcell. Biochem.51, 439–466 (2010)

    Article CAS  Google Scholar 

  16. Liu, C. et al. Identification of relaxin-3/INSL7 as an endogenous ligand for the orphan G-protein-coupled receptor GPCR135.J. Biol. Chem.278, 50754–50764 (2003)

    Article CAS  Google Scholar 

  17. Lund, E. G., Kerr, T. A., Sakai, J., Li, W. P. & Russell, D. W. cDNA cloning of mouse and human cholesterol 25-hydroxylases, polytopic membrane proteins that synthesize a potent oxysterol regulator of lipid metabolism.J. Biol. Chem.273, 34316–34327 (1998)

    Article CAS  Google Scholar 

  18. Cali, J. J. & Russell, D. W. Characterization of human sterol 27-hydroxylase. A mitochondrial cytochrome P-450 that catalyzes multiple oxidation reaction in bile acid biosynthesis.J. Biol. Chem.266, 7774–7778 (1991)

    CAS PubMed  Google Scholar 

  19. Diczfalusy, U. et al. Marked upregulation of cholesterol 25-hydroxylase expression by lipopolysaccharide.J. Lipid Res.50, 2258–2264 (2009)

    Article CAS  Google Scholar 

  20. Bauman, D. R. et al. 25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production.Proc. Natl Acad. Sci. USA106, 16764–16769 (2009)

    Article ADS CAS  Google Scholar 

  21. Napolitani, G., Rinaldi, A., Bertoni, F., Sallusto, F. & Lanzavecchia, A. Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1–polarizing program in dendritic cells.Nature Immunol.6, 769–776 (2005)

    Article CAS  Google Scholar 

  22. Reif, K. et al. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position.Nature416, 94–99 (2002)

    Article ADS  Google Scholar 

  23. Kelly, E., Bailey, C. P. & Henderson, G. Agonist-selective mechanisms of GPCR desensitization.Br. J. Pharmacol.153, S379–S388 (2008)

    Article CAS  Google Scholar 

  24. Walzer, T. et al. Identification, activation, and selectivein vivo ablation of mouse NK cells via NKp46.Proc. Natl Acad. Sci. USA104, 3384–3389 (2007)

    Article ADS CAS  Google Scholar 

  25. Kesteman, N., Vansanten, G., Pajak, B., Goyert, S. M. & Moser, M. Injection of lipopolysaccharide induces the migration of splenic neutrophils to the T cell area of the white pulp: role of CD14 and CXC chemokines.J. Leukoc. Biol.83, 640–647 (2008)

    Article CAS  Google Scholar 

  26. Hannedouche, S. et al. Oxysterols direct immune cell migration via EBI2.Nature 10.1038/10280 (2011)

  27. Li, D. & Spencer, T. A. Synthesis of 7α-hydroxy derivatives of regulatory sterols.Steroids65, 529–535 (2000)

    Article CAS  Google Scholar 

  28. Sˇt’astná, E. et al. Stereoselectivity of sodium borohydride reduction of saturated steroidal ketones using conditions of Luche reduction.Steroids75, 721–725 (2010)

    Article  Google Scholar 

  29. Kumar, B. S. et al. Gas chromatography-mass spectrometry-based simultaneous quantitative analytical method for urinary oxysterols and bile acids in rats.Anal. Biochem.408, 242–252 (2011)

    Article CAS  Google Scholar 

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Acknowledgements

We thank J. Palmer and J. Blevitt for microscopic image acquisition. We thank J. Zhu, R. Luna and S. Nguyen for technical assistance and J. Cowden for scientific discussions.

Author information

Author notes

  1. Ning Qin & Lars Karlsson

    Present address: Present addresses: Roche R&D Center (China) Ltd., 720 Cai Lun Road, Building 5, Zhangjiang High-Tech Park, Pudong, Shanghai 201203, China (N.Q.); Regulus Therapeutics, 3545 John Hopkins Court, San Diego, California 92121, USA (L.K.).,

Authors and Affiliations

  1. Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, 92121, California, USA

    Changlu Liu, Xia V. Yang, Jiejun Wu, Chester Kuei, Neelakandha S. Mani, Li Zhang, Jingxue Yu, Steven W. Sutton, Ning Qin, Homayon Banie, Lars Karlsson, Siquan Sun & Timothy W. Lovenberg

Authors
  1. Changlu Liu
  2. Xia V. Yang
  3. Jiejun Wu
  4. Chester Kuei
  5. Neelakandha S. Mani
  6. Li Zhang
  7. Jingxue Yu
  8. Steven W. Sutton
  9. Ning Qin
  10. Homayon Banie
  11. Lars Karlsson
  12. Siquan Sun
  13. Timothy W. Lovenberg

Contributions

C.L., S.S., J.W., X.V.Y., N.S.M., N.Q., L.K. and T.W.L. designed and conceptualized the research. C.L., S.S., J.W., X.V.Y., N.S.M., C.K., J.Y., S.W.S., N.Q., L.Z. and H.B. performed experiments. C.L., S.S., J.W., X.V.Y., N.S.M., C.K., L.Z., N.Q, L.K. and T.W.L. analysed the data, prepared the figures and wrote the manuscript.

Corresponding author

Correspondence toChanglu Liu.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Tables 1-2, Supplementary Figures 1-17 with legends and Supplementary Methods. (PDF 1381 kb)

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Liu, C., Yang, X., Wu, J.et al. Oxysterols direct B-cell migration through EBI2.Nature475, 519–523 (2011). https://doi.org/10.1038/nature10226

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Editorial Summary

EBI2 receptors revealed as oxysterols

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.

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