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Oxysterols direct immune cell migration via EBI2

机译:氧固醇通过EBI2指导免疫细胞迁移

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摘要

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~(1-3). 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-3p,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)~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 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.
机译:爱泼斯坦-巴尔病毒诱导的基因2(EBI2,也称为GPR183)是体液免疫反应所必需的G蛋白偶联受体。受体的多态性与炎性自身免疫疾病有关(1-3)。 EBI2的天然配体是未知的。在这里,我们描述了将7α,25-二羟基胆固醇(也称为7α,25-OHC或5-cholesten-3p,7α,25-三醇)鉴定为EBI2的有效和选择性激动剂。通过监测第二信使读数和可饱和的高亲和力放射性配体结合,验证了7α,25-OHC和紧密相关的氧固醇对人EBI2的功能激活。此外,我们发现7α,25-OHC和密切相关的氧固醇通过指导细胞在体内外的迁移,充当表达EBI2的免疫细胞的趋化因子。产生7α,25-OHC所需的关键酶是胆固醇25-羟化酶(CH25H)〜4。与EBI2受体敲除小鼠相似,缺乏CH25H的小鼠在免疫激发后无法将活化的B细胞在脾脏中定位到外部滤泡,并降低了浆细胞的反应。这表明CH25H在体内产生EBI2生物活性,并表明EBI2-氧固醇信号通路在适应性免疫应答中具有重要作用。

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  • 来源
    《Nature》 |2011年第7357期|p.524-527|共4页
  • 作者单位

    Euroscreen SA, 6041 Gosselies, Belgium;

    Analytical Sciences, Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland;

    Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, California 94143-0414, USA;

    Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA,Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA;

    Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA;

    Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, California 94143-0414, USA;

    Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland;

    Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland;

    Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 4056 Basel,Switzerland;

    Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA;

    Analytical Sciences, Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland;

    Euroscreen SA, 6041 Gosselies, Belgium;

    Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 4056 Basel,Switzerland;

    Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, California 94143-0414, USA;

    Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland;

    Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland;

    Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland;

    Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 4056 Basel,Switzerland;

    Analytical Sciences, Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland;

    Analytical Sciences, Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland;

    Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA;

    Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA;

    Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland;

    Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA;

    Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA;

    Analytical Sciences, Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland;

    Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland;

    Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 4056 Basel,Switzerland;

    Euroscreen SA, 6041 Gosselies, Belgium;

    Euroscreen SA, 6041 Gosselies, Belgium;

    Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA;

    Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA;

    Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA;

    Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland;

    Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, California 94143-0414, USA;

    Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland;

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