Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

25-Hydroxycholesterols in innate and adaptive immunity

Nature Reviews Immunology volume 14, pages 731–743 (2014)Cite this article

Subjects

Key Points

  • The oxysterols 25-hydroxycholesterol (25-HC) and 7α,25-dihydroxycholesterol (7α,25-HC) are made by a range of cell types in lymphoid and non-lymphoid tissues, and their production is upregulated by inflammatory stimuli.

  • The ability of 25-HC to regulate the synthesis and compartmentalization of lipids enables it to antagonize the replication of a wide diversity of viruses.

  • 25-HC functions downstream of interferon (IFN) signalling to suppress interleukin-1β (IL-1β) expression and inflammasome activity. This mechanism of IFN-mediated feedback regulation of inflammation occurs at least in part through 25-HC-mediated suppression of sterol response element-binding protein (SREBP) processing.

  • 25-HC augments the expression of some inflammatory cytokines, including IL-6. The mechanisms by which the anti-inflammatory and pro-inflammatory actions of 25-HC might be coordinated are discussed.

  • 7α,25-HC, the most potent ligand of the G protein-coupled receptor EBI2 (also known as GPR183), guides the migration of B cells and dendritic cells to interfollicular regions of lymphoid tissues. EBI2 and 7α,25-HC deficiency both cause defective antibody responses.

  • A model is discussed in which 25-HC and 7α,25-HC produced in overlapping zones might function in a coordinated manner to recruit EBI2+ cells, promote their resistance to viral infection and control their cytokine production.

Abstract

Cholesterol and components of the cholesterol biosynthetic pathway have fundamental roles in all mammalian cells. Hydroxylated forms of cholesterol are now emerging as important regulators of immune function. This involves effects on the cholesterol biosynthetic pathway and cell membrane properties, which can have antiviral and anti-inflammatory influences. In addition, a dihydroxylated form of cholesterol functions as an immune cell guidance cue by engaging the G protein-coupled receptor EBI2, and it is required for mounting adaptive immune responses. In this Review, we summarize the current understanding of the closely related oxysterols 25-hydroxycholesterol and 7α,25-dihydroxycholesterol, and the growing evidence that they have wide-ranging influences on innate and adaptive immunity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Pathway of cholesterol and non-sterol isoprene biosynthesis.
Figure 2: Enzymatic steps involved in the generation of oxysterols from cholesterol.
Figure 3: Pathway of SREBP regulation by cholesterol and 25-HC.
Figure 4: Summary of the antiviral activities of 25-HC.
Figure 5: Inflammation-regulatory activities of 25-HC.
Figure 6: EBI2 guides naive and activated B cell positioning.
Figure 7: Models to account for how 25-HC and 7α,25-HC distribution in tissues may be regulated and influence the migration of EBI2-expressing cells.

Similar content being viewed by others

References

  1. Ikonen, E. Cellular cholesterol trafficking and compartmentalization. Nature Rev. Mol. Cell. Biol. 9, 125–138 (2008).

    Article  CAS  Google Scholar 

  2. Simons, K. & Gerl, M. J. Revitalizing membrane rafts: new tools and insights. Nature Rev. Mol. Cell. Biol. 11, 688–699 (2010).

    Article  CAS  Google Scholar 

  3. Heaton, N. S. & Randall, G. Multifaceted roles for lipids in viral infection. Trends Microbiol. 19, 368–375 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chukkapalli, V., Heaton, N. S. & Randall, G. Lipids at the interface of virus-host interactions. Curr. Opin. Microbiol. 15, 512–518 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Goldstein, J. L., DeBose-Boyd, R. A. & Brown, M. S. Protein sensors for membrane sterols. Cell 124, 35–46 (2006). This is a concise review on the pioneering work that defined the molecular mechanism of cholesterol-mediated and 25-HC-mediated feedback regulation of the sterol biosynthetic pathway.

    Article  CAS  PubMed  Google Scholar 

  6. Russell, D. W. Oxysterol biosynthetic enzymes. Biochim. Biophys. Acta 1529, 126–135 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Russell, D. W. The enzymes, regulation, and genetics of bile acid synthesis. Annu. Rev. Biochem. 72, 137–174 (2003). This authoritative review describes the enzyme requirements for the synthesis of bile acids and oxysterols in the liver and other tissues.

    Article  CAS  PubMed  Google Scholar 

  8. Brown, M. S. & Goldstein, J. L. Suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and inhibition of growth of human fibroblasts by 7-ketocholesterol. J. Biol. Chem. 249, 7306–7314 (1974).

    Article  CAS  PubMed  Google Scholar 

  9. Kandutsch, A. A. & Chen, H. W. Inhibition of sterol synthesis in cultured mouse cells by cholesterol derivatives oxygenated in the side chain. J. Biol. Chem. 249, 6057–6061 (1974).

    Article  CAS  PubMed  Google Scholar 

  10. Bjorkhem, I. Are side-chain oxidized oxysterols regulators also in vivo? J. Lipid Res. 50, S213–S218 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Diczfalusy, U. On the formation and possible biological role of 25-hydroxycholesterol. Biochimie 95, 455–460 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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. USA 106, 16764–16769 (2009). This paper is an early demonstration that 25-HC can affect the adaptive immune system with the discovery of increased IgA levels in CH25H-deficient mice and decreased IgA levels in CYP7B1-deficient mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Park, K. & Scott, A. L. Cholesterol 25-hydroxylase production by dendritic cells and macrophages is regulated by type I interferons. J. Leukoc. Biol. 88, 1081–1087 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zou, T., Garifulin, O., Berland, R. & Boyartchuk, V. L. Listeria monocytogenes infection induces prosurvival metabolic signaling in macrophages. Infect. Immun. 79, 1526–1535 (2011). This study shows that L. monocytogenes infection and type I IFN treatment of macrophages upregulate Ch25h and this leads to the repression of caspase 1 activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Blanc, M. et al. The transcription factor STAT-1 couples macrophage synthesis of 25-hydroxycholesterol to the interferon antiviral response. Immunity 38, 106–118 (2013). This study shows that 25-HC is strongly induced following viral infection and by IFN, and has a broad ability to antagonize the replication of enveloped viruses in vitro.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liu, S. Y. et al. Interferon-inducible cholesterol-25- hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity 38, 92–105 (2013). This study is complementary to reference 16 and shows that CH25H and 25-HC inhibit the replication of a wide range of enveloped viruses in vitro , as well as demonstrating the in vivo effects of 25-HC and CH25H deficiency on viral replication.

    Article  PubMed  CAS  Google Scholar 

  18. 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. Immunity 31, 259–269 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Pereira, J. P., Kelly, L. M., Xu, Y. & Cyster, J. G. EBI2 mediates B cell segregation between the outer and centre follicle. Nature 460, 1122–1126 (2009). References 18 and 19 show, using independently generated EBI2-deficient mice, an in vivo function for EBI2 in guiding immune cell migration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hannedouche, S. et al. Oxysterols direct immune cell migration via EBI2. Nature 475, 524–527 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liu, C. et al. Oxysterols direct B-cell migration through EBI2. Nature 475, 519–523 (2011). References 20 and 21 both use classical biochemical methods to de-orphanize EBI2 and identify 7α,25-HC as the most potent ligand.

    Article  CAS  PubMed  Google Scholar 

  22. Gold, E. S. et al. ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol-induced lipid body formation. J. Exp. Med. 209, 807–817 (2012). This study shows that Ch25h is a major target gene repressed by ATF3 and that increased levels of 25-HC in the absence of ATF3 are associated with macrophage foam cell formation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gold, E. S. et al. 25-Hydroxycholesterol acts as an amplifier of inflammatory signaling. Proc. Natl Acad. Sci. USA 111, 10666–10671 (2014). This study shows that 25-HC can augment the expression of some inflammatory genes in macrophages and correlates these findings with reduced inflammation-mediated pathology following influenza virus infection in CH25H-deficient mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Koarai, A. et al. 25-Hydroxycholesterol enhances cytokine release and Toll-like receptor 3 response in airway epithelial cells. Respir. Res. 13, 63 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Reboldi, A. et al. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon. Science 345, 679–684 (2014). This study shows that CH25H deficiency leads to the increased production of IL-1 family cytokines following inflammatory insults in vivo , and demonstrates that 25-HC represses Il1b expression and inflammasome activation in activated macrophages.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gatto, D. et al. The chemotactic receptor EBI2 regulates the homeostasis, localization and immunological function of splenic dendritic cells. Nature Immunol. 14, 446–453 (2013).

    Article  CAS  Google Scholar 

  27. Yi, T. & Cyster, J. G. EBI2-mediated bridging channel positioning supports splenic dendritic cell homeostasis and particulate antigen capture. Elife 2, e00757 (2013). References 26 and 27 establish that CD4+ DCs in the spleen require EBI2 and 7α,25-HC for positioning in marginal zone bridging channels, and show that this positioning is important for maintaining their homeostasis and for mounting T cell-dependent antibody responses against certain blood-borne antigens.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. 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  PubMed  Google Scholar 

  29. Stiles, A. R., McDonald, J. G., Bauman, D. R. & Russell, D. W. CYP7B1: one cytochrome P450, two human genetic diseases, and multiple physiological functions. J. Biol. Chem. 284, 28485–28489 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Schwarz, M. et al. The bile acid synthetic gene 3β-hydroxy-δ5-C27-steroid oxidoreductase is mutated in progressive intrahepatic cholestasis. J. Clin. Invest. 106, 1175–1184 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yi, T. et al. Oxysterol gradient generation by lymphoid stromal cells guides activated B cell movement during humoral responses. Immunity 37, 535–548 (2012). This study demonstrates that CH25H and CYP7B1 are abundant in interfollicular stromal cells and low in the central region of follicles. It also shows that HSD3B7 is needed to inactivate 7α,25-HC as an EBI2 ligand and thereby establish 7α,25-HC 'gradients' that guide cell movement.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Brown, M. S. & Goldstein, J. L. Cholesterol feedback: from Schoenheimer's bottle to Scap's MELADL. J. Lipid Res. 50, S15–S27 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Spann, N. J. & Glass, C. K. Sterols and oxysterols in immune cell function. Nature Immunol. 14, 893–900 (2013).

    Article  CAS  Google Scholar 

  34. Sever, N., Yang, T., Brown, M. S., Goldstein, J. L. & DeBose-Boyd, R. A. Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain. Mol. Cell 11, 25–33 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Mackenzie, J. M., Khromykh, A. A. & Parton, R. G. Cholesterol manipulation by West Nile virus perturbs the cellular immune response. Cell Host Microbe 2, 229–239 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Rothwell, C. et al. Cholesterol biosynthesis modulation regulates dengue viral replication. Virology 389, 8–19 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Robinzon, S. et al. Impaired cholesterol biosynthesis in a neuronal cell line persistently infected with measles virus. J. Virol. 83, 5495–5504 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Petersen, J. et al. The major cellular sterol regulatory pathway is required for Andes virus infection. PLoS Pathog. 10, e1003911 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Lu, Y. E., Cassese, T. & Kielian, M. The cholesterol requirement for sindbis virus entry and exit and characterization of a spike protein region involved in cholesterol dependence. J. Virol. 73, 4272–4278 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Danthi, P. & Chow, M. Cholesterol removal by methyl-β-cyclodextrin inhibits poliovirus entry. J. Virol. 78, 33–41 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Daya, M., Cervin, M. & Anderson, R. Cholesterol enhances mouse hepatitis virus-mediated cell fusion. Virology 163, 276–283 (1988).

    Article  CAS  PubMed  Google Scholar 

  42. Phalen, T. & Kielian, M. Cholesterol is required for infection by Semliki Forest virus. J. Cell Biol. 112, 615–623 (1991).

    Article  CAS  PubMed  Google Scholar 

  43. Blanc, M. et al. Host defense against viral infection involves interferon mediated down-regulation of sterol biosynthesis. PLoS Biol. 9, e1000598 (2011). This study demonstrates that several viral infections and type I IFNs repress SREBP2 cleavage and sterol biosynthesis in macrophages and fibroblasts.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shibata, N. et al. 25-Hydroxycholesterol activates the integrated stress response to reprogram transcription and translation in macrophages. J. Biol. Chem. 288, 35812–35823 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu, S. Y., Sanchez, D. J., Aliyari, R., Lu, S. & Cheng, G. Systematic identification of type I and type II interferon-induced antiviral factors. Proc. Natl Acad. Sci. USA 109, 4239–4244 (2012). This study identifies CH25H as a major ISG that has antiviral activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Moog, C., Aubertin, A. M., Kirn, A. & Luu, B. Oxysterols, but not cholesterol, inhibit human immunodeficiency virus replication in vitro. Antivir. Chem. Chemother. 9, 491–496 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Su, A. I. et al. Genomic analysis of the host response to hepatitis C virus infection. Proc. Natl Acad. Sci. USA 99, 15669–15674 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Arita, M. et al. Oxysterol-binding protein family I is the target of minor enviroxime-like compounds. J. Virol. 87, 4252–4260 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gale, S. E. et al. Side chain oxygenated cholesterol regulates cellular cholesterol homeostasis through direct sterol-membrane interactions. J. Biol. Chem. 284, 1755–1764 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Olsen, B. N., Schlesinger, P. H., Ory, D. S. & Baker, N. A. 25-Hydroxycholesterol increases the availability of cholesterol in phospholipid membranes. Biophys. J. 100, 948–956 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chang, T. Y., Chang, C. C., Ohgami, N. & Yamauchi, Y. Cholesterol sensing, trafficking, and esterification. Annu. Rev. Cell Dev. Biol. 22, 129–157 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Arita, M. Phosphatidylinositol-4 kinase III β and oxysterol-binding protein accumulate unesterified cholesterol on poliovirus-induced membrane structure. Microbiol. Immunol. 58, 239–256 (2014).

    Article  CAS  PubMed  Google Scholar 

  53. Mesmin, B. et al. A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP. Cell 155, 830–843 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Amini- Bavil-Olyaee, S. et al. The antiviral effector IFITM3 disrupts intracellular cholesterol homeostasis to block viral entry. Cell Host Microbe 13, 452–464 (2013).

    Article  CAS  Google Scholar 

  55. Trinchieri, G. Type I interferon: friend or foe? J. Exp. Med. 207, 2053–2063 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gonzalez-Navajas, J. M., Lee, J., David, M. & Raz, E. Immunomodulatory functions of type I interferons. Nature Rev. Immunol. 12, 125–135 (2012).

    Article  CAS  Google Scholar 

  57. Ludigs, K., Parfenov, V., Du Pasquier, R. A. & Guarda, G. Type I IFN-mediated regulation of IL-1 production in inflammatory disorders. Cell. Mol. Life Sci. 69, 3395–3418 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Inoue, M. & Shinohara, M. L. The role of interferon-β in the treatment of multiple sclerosis and experimental autoimmune encephalomyelitis — in the perspective of inflammasomes. Immunology 139, 11–18 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Guarda, G. et al. Type I interferon inhibits interleukin-1 production and inflammasome activation. Immunity 34, 213–223 (2011). This is an elegant study demonstrating that type I IFN suppresses inflammasome activation by an undefined mechanism.

    Article  CAS  PubMed  Google Scholar 

  60. Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Franchi, L., Munoz-Planillo, R. & Nunez, G. Sensing and reacting to microbes through the inflammasomes. Nature Immunol. 13, 325–332 (2012).

    Article  CAS  Google Scholar 

  62. Kuijk, L. M. et al. HMG-CoA reductase inhibition induces IL-1β release through Rac1/PI3K/PKB-dependent caspase-1 activation. Blood 112, 3563–3573 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Liao, Y. H. et al. HMG-CoA reductase inhibitors activate caspase-1 in human monocytes depending on ATP release and P2X7 activation. J. Leukoc. Biol. 93, 289–299 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Mayer-Barber, K. D. et al. Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk. Nature 511, 99–103 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Berry, M. P. et al. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature 466, 973–977 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Masters, S. L., Simon, A., Aksentijevich, I. & Kastner, D. L. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*). Annu. Rev. Immunol. 27, 621–668 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mandey, S. H., Kuijk, L. M., Frenkel, J. & Waterham, H. R. A role for geranylgeranylation in interleukin-1β secretion. Arthritis Rheum. 54, 3690–3695 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Pontillo, A., Paoluzzi, E. & Crovella, S. The inhibition of mevalonate pathway induces upregulation of NALP3 expression: new insight in the pathogenesis of mevalonate kinase deficiency. Eur. J. Hum. Genet. 18, 844–847 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kim, J. et al. Sufficient production of geranylgeraniol is required to maintain endotoxin tolerance in macrophages. J. Lipid Res. 54, 3430–3437 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gibson, K. M. et al. 3-Hydroxy-3-methylglutaryl coenzyme A reductase activity in cultured fibroblasts from patients with mevalonate kinase deficiency: differential response to lipid supplied by fetal bovine serum in tissue culture medium. J. Lipid Res. 31, 515–521 (1990).

    Article  CAS  PubMed  Google Scholar 

  71. Umetani, M. et al. The cholesterol metabolite 27-hydroxycholesterol promotes atherosclerosis via proinflammatory processes mediated by estrogen receptor alpha. Cell. Metab. 20, 172–182 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Umetani, M. et al. 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nature Med. 13, 1185–1192 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Lundberg, B. Chemical composition and physical state of lipid deposits in atherosclerosis. Atherosclerosis 56, 93–110 (1985).

    Article  CAS  PubMed  Google Scholar 

  74. Brown, A. J. & Jessup, W. Oxysterols and atherosclerosis. Atherosclerosis 142, 1–28 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Brown, M. S., Dana, S. E. & Goldstein, J. L. Cholesterol ester formation in cultured human fibroblasts. Stimulation by oxygenated sterols. J. Biol. Chem. 250, 4025–4027 (1975).

    Article  CAS  PubMed  Google Scholar 

  76. Miller, S. C. & Melnykovych, G. Regulation of cholesterol biosynthesis and esterification by 25-hydroxycholesterol in a macrophage-like cell line: uncoupling by progesterone. J. Lipid Res. 25, 991–999 (1984).

    Article  CAS  PubMed  Google Scholar 

  77. Cheng, D., Chang, C. C., Qu, X. & Chang, T. Y. Activation of acyl-coenzyme A:cholesterol acyltransferase by cholesterol or by oxysterol in a cell-free system. J. Biol. Chem. 270, 685–695 (1995).

    Article  CAS  PubMed  Google Scholar 

  78. Li-Hawkins, J., Lund, E. G., Turley, S. D. & Russell, D. W. Disruption of the oxysterol 7α-hydroxylase gene in mice. J. Biol. Chem. 275, 16536–16542 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Gilchrist, M. et al. Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature 441, 173–178 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. McDonald, J. G. & Russell, D. W. 25-Hydroxycholesterol: a new life in immunology. J. Leukoc. Biol. 88, 1071–1072 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Rosenkilde, M. M. et al. Molecular pharmacological phenotyping of EBI2. An orphan seven-transmembrane receptor with constitutive activity. J. Biol. Chem. 281, 13199–13208 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Benned-Jensen, T. et al. Ligand modulation of the Epstein-Barr virus-induced seven-transmembrane receptor EBI2: identification of a potent and efficacious inverse agonist. J. Biol. Chem. 286, 29292–29302 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Benned-Jensen, T. et al. Small molecule antagonism of oxysterol-induced Epstein-Barr virus induced gene 2 (EBI2) activation. FEBS Open Bio. 3, 156–160 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Benned-Jensen, T. & Rosenkilde, M. M. Structural motifs of importance for the constitutive activity of the orphan 7TM receptor EBI2: analysis of receptor activation in the absence of an agonist. Mol. Pharmacol. 74, 1008–1021 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Benned-Jensen, T. et al. Molecular characterization of oxysterol binding to the Epstein-Barr virus-induced gene 2 (GPR183). J. Biol. Chem. 287, 35470–35483 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhang, L. et al. Identification of structural motifs critical for Epstein-Barr virus-induced molecule 2 function and homology modeling of the ligand docking site. Mol. Pharmacol. 82, 1094–1103 (2012).

    Article  CAS  PubMed  Google Scholar 

  88. Hanson, M. A. et al. Crystal structure of a lipid G protein-coupled receptor. Science 335, 851–855 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Gessier, F. et al. Identification and characterization of small molecule modulators of the Epstein-Barr virus-induced gene 2 (EBI2) receptor. J. Med. Chem. 57, 3358–3368 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Gatto, D. & Brink, R. B cell localization: regulation by EBI2 and its oxysterol ligand. Trends Immunol. 34, 336–341 (2013). This is an excellent review of EBI2 biology in B cells.

    Article  CAS  PubMed  Google Scholar 

  91. Kelly, L. M., Pereira, J. P., Yi, T., Xu, Y. & Cyster, J. G. EBI2 guides serial movements of activated B cells and ligand activity is detectable in lymphoid and nonlymphoid tissues. J. Immunol. 187, 3026–3032 (2011). This study establishes the time course of EBI2 influence on B cell behaviour in vivo and uses a sensitive bioassay to show that an EBI2 ligand is widely distributed in tissues.

    Article  CAS  PubMed  Google Scholar 

  92. Gatto, D., Wood, K. & Brink, R. EBI2 operates independently of but in cooperation with CXCR5 and CCR7 to direct B cell migration and organization in follicles and the germinal center. J. Immunol. 187, 4621–4628 (2011). By removing the influence of two major chemokines, this report reveals additional influences of EBI2 in B cell positioning in the spleen.

    Article  CAS  PubMed  Google Scholar 

  93. Chan, T. D. et al. Antigen affinity controls rapid T-dependent antibody production by driving the expansion rather than the differentiation or extrafollicular migration of early plasmablasts. J. Immunol. 183, 3139–3149 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. MacLennan, I. & Vinuesa, C. Dendritic cells, BAFF, and APRIL: innate players in adaptive antibody responses. Immunity 17, 235–238 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Xu, W. & Banchereau, J. The antigen presenting cells instruct plasma cell differentiation. Front. Immunol. 4, 504 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Mueller, S. N. & Germain, R. N. Stromal cell contributions to the homeostasis and functionality of the immune system. Nature Rev. Immunol. 9, 618–629 (2009).

    Article  CAS  Google Scholar 

  97. Coffey, F., Alabyev, B. & Manser, T. Initial clonal expansion of germinal center B cells takes place at the perimeter of follicles. Immunity 30, 599–609 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Cyster, J. G. B cell follicles and antigen encounters of the third kind. Nature Immunol. 11, 989–996 (2010).

    Article  CAS  Google Scholar 

  99. Shaffer, A. L. et al. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13, 199–212 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Turqueti-Neves, A. et al. B-cell-intrinsic STAT6 signaling controls germinal center formation. Eur. J. Immunol. 44, 2130–2138 (2014).

    Article  CAS  PubMed  Google Scholar 

  101. Kawamoto, S. et al. Foxp3+ T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity 41, 152–165 (2014).

    Article  CAS  PubMed  Google Scholar 

  102. Coelho, F. M. et al. Naive B-cell trafficking is shaped by local chemokine availability and LFA-1-independent stromal interactions. Blood 121, 4101–4109 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. Barroso, R. et al. EBI2 regulates CXCL13-mediated responses by heterodimerization with CXCR5. FASEB J. 26, 4841–4854 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Lund, R., Aittokallio, T., Nevalainen, O. & Lahesmaa, R. Identification of novel genes regulated by IL-12, IL-4, or TGF-β during the early polarization of CD4+ lymphocytes. J. Immunol. 171, 5328–5336 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Kroenke, M. A. et al. Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation. J. Immunol. 188, 3734–3744 (2012).

    Article  CAS  PubMed  Google Scholar 

  106. Kraal, G. & Mebius, R. New insights into the cell biology of the marginal zone of the spleen. Int. Rev. Cytol. 250, 175–215 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kabashima, K. et al. Intrinsic lymphotoxin-β receptor requirement for homeostasis of lymphoid tissue dendritic cells. Immunity 22, 439–450 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Heinig, M. et al. A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature 467, 460–464 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wallace, C. et al. Statistical colocalization of monocyte gene expression and genetic risk variants for type 1 diabetes. Hum. Mol. Genet. 21, 2815–2824 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Jostins, L. et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Chiang, E. Y., Johnston, R. J. & Grogan, J. EBI2 is a negative regulator of type I interferons in plasmacytoid and myeloid dendritic cells. PLoS ONE 8, e83457 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Nau, G. J. et al. Human macrophage activation programs induced by bacterial pathogens. Proc. Natl Acad. Sci. USA 99, 1503–1508 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Preuss, I. et al. Transcriptional regulation and functional characterization of the oxysterol/EBI2 system in primary human macrophages. Biochem. Biophys. Res. Commun. 446, 663–668 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. Cantor, R. M. et al. Systemic lupus erythematosus genome scan: support for linkage at 1q23, 2q33, 16q12–13, and 17q21–23 and novel evidence at 3p24, 10q23–24, 13q32, and 18q22–23. Arthritis Rheumatism 50, 3203–3210 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Moser, K. L. et al. Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. Proc. Natl Acad. Sci. USA 95, 14869–14874 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ye, S. et al. Protein interaction for an interferon-inducible systemic lupus associated gene, IFIT1. Rheumatology 42, 1155–1163 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Pascual, V., Chaussabel, D. & Banchereau, J. A genomic approach to human autoimmune diseases. Annu. Rev. Immunol. 28, 535–571 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Wilson, L. E., Widman, D., Dikman, S. H. & Gorevic, P. D. Autoimmune disease complicating antiviral therapy for hepatitis C virus infection. Semin. Arthritis Rheum. 32, 163–173 (2002).

    Article  PubMed  Google Scholar 

  119. Niedobitek, G. et al. Patterns of Epstein-Barr virus infection in non-neoplastic lymphoid tissue. Blood 79, 2520–2526 (1992).

    Article  CAS  PubMed  Google Scholar 

  120. Kurth, J. et al. EBV-infected B cells in infectious mononucleosis: viral strategies for spreading in the B cell compartment and establishing latency. Immunity 13, 485–495 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Hanlon, P., Avenell, A., Aucott, L. & Vickers, M. A. Systematic review and meta-analysis of the sero-epidemiological association between Epstein-Barr virus and systemic lupus erythematosus. Arthritis Res. Ther. 16, R3 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Lin, C. Y. & Morel, D. W. Esterification of oxysterols in human serum: effects on distribution and cellular uptake. J. Lipid Res. 37, 168–178 (1996).

    Article  CAS  PubMed  Google Scholar 

  123. Frederico, B., Chao, B., May, J. S., Belz, G. T. & Stevenson, P. G. A murid gamma-herpesviruses exploits normal splenic immune communication routes for systemic spread. Cell Host Microbe 15, 457–470 (2014).

    Article  CAS  PubMed  Google Scholar 

  124. Janowski, B. A., Willy, P. J., Devi, T. R., Falck, J. R. & Mangelsdorf, D. J. An oxysterol signalling pathway mediated by the nuclear receptor LXRα. Nature 383, 728–731 (1996).

    Article  CAS  PubMed  Google Scholar 

  125. Bensinger, S. J. & Tontonoz, P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature 454, 470–477 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Soroosh, P. et al. Oxysterols are agonist ligands of RORγt and drive Th1 cell differentiation. Proc. Natl Acad. Sci. USA 111, 12163–12168 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Huh, J. R. et al. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity. Nature 472, 486–490 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Kidani, Y. et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nature Immunol. 14, 489–499 (2013).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank R. Locksley and D. Russell for comments on the manuscript. Work from the Cyster laboratory discussed in this Review was supported in part by the US National Institutes of Health (grant AI40098) and a grant from the American Asthma Foundation.

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, University of California, San Francisco, 94143–0414, California, USA

    Jason G. Cyster, Eric V. Dang, Andrea Reboldi & Tangsheng Yi

  2. Howard Hughes Medical Institute, University of California, San Francisco, 94143–0414, California, USA

    Jason G. Cyster

  3. Department of Discovery Immunology, Genentech, South San Francisco, 94080, California, USA

    Tangsheng Yi

Authors
  1. Jason G. Cyster
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric V. Dang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea Reboldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tangsheng Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jason G. Cyster or Tangsheng Yi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Isoprenoids

Hydrocarbons composed of two or more isoprene units; an isoprene is a five-carbon unit with the formula: CH2 = C(CH3)CH = CH2.

Oxysterols

Derivatives of cholesterol with a hydroxyl group in addition to the 3β-hydroxyl group.

Bile acids

Highly modified forms of cholesterol that are secreted into the intestine to promote the solubilization and uptake of dietary lipids, in addition to functioning as the only known mechanism to excrete cholesterol from the body.

Sterol response element-binding proteins

(SREBPs). Transcription factors that begin as multi-transmembrane endoplasmic reticulum proteins and are cleaved in the Golgi to release the basic helix–loop–helix leucine zipper transcription factor domain that binds to sterol regulatory elements in DNA.

3-hydroxy-3-methylglutaryl-CoA reductase

(HMGCR). Also known as HMG-CoA reductase. The rate-controlling enzyme of the mevalonate pathway, which is the metabolic pathway that produces isoprenoids and cholesterol.

SREBP cleavage-activating protein

(SCAP). A multi-transmembrane endoplasmic reticulum protein that contains a sterol-sensing domain and that binds to sterol response element-binding proteins (SREBPs) and escorts them to the Golgi when cholesterol or 25-hydroxycholesterol levels are low.

IFN-stimulated genes

(ISGs). Genes that are directly induced by signalling from the type I interferon (IFN) receptor.

Prenylation

A post-translational modification that involves the attachment of an isoprenoid (farnesyl or geranylgeranyl) lipid to a protein.

Integrated stress response

A cellular stress response pathway initiated by one of the four eukaryotic translation initiation factor 2α kinases.

Oxysterol-binding protein

(OSBP). An intracellular protein named because of its ability to bind 25-hydroxycholesterol as well as cholesterol. It functions in the exchange of cholesterol and phosphatidylinositol 4-phosphate between the endoplasmic reticulum and the Golgi.

Inflammasome

A large multiprotein complex consisting of ASC, caspase 1 and at least one activator, such as NOD-, LRR- and pyrin domain-containing 3 (NLRP3), NOD-, LRR- and CARD-containing 4 (NLRC4) or absent in melanoma 2 (AIM2).

Statins

Cholesterol-lowering drugs that function by inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase.

Experimental autoimmune encephalomyelitis

An inflammatory disease of the central nervous system that models human multiple sclerosis and is induced by immunizing with a myelin autoantigen in a strong adjuvant.

Marginal zone bridging channels

Specialized interfollicular regions that connect the T cell zone and red pulp in the spleen.

Retinoic acid receptor-related orphan receptor-γt

(RORγt). A nuclear hormone receptor that is important for the development of interleukin-17-producing T cells, for thymocyte maturation and for the development of lymphoid tissue inducer cells.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cyster, J., Dang, E., Reboldi, A. et al. 25-Hydroxycholesterols in innate and adaptive immunity. Nat Rev Immunol 14, 731–743 (2014). https://doi.org/10.1038/nri3755

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3755

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing