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Oxysterols direct B-cell migration through EBI2

机译：氧固醇通过EBI2指导B细胞迁移

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摘要

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"6. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol metabolism7"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-OHC in 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-acti-vated 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.
机译：EBI2（也称为GPR183）是一种孤儿G蛋白偶联受体，在脾脏中高表达，并在爱泼斯坦-巴尔病毒感染后被上调1。最近的研究表明，该受体控制卵泡B细胞迁移和T细胞依赖性抗体的产生[2]。6。氧固醇对免疫和炎症反应以及胆固醇代谢产生深远的影响[7] 9。氧固醇的生物学作用在很大程度上归因于核激素受体的激活[10'11]。在这里，我们从猪脾提取物中分离出氧固醇，并表明它们是EBI2的内源性配体。最有效的配体和活化剂是7α，25-二羟基胆固醇（OHC），对于EBI2的解离常数为450 pM。在体外，7α，25-OHC刺激表达EBI2的小鼠B和T细胞迁移，其最大有效浓度值约为500 pM，但对EBI2缺陷细胞没有影响。在体内，EBI2缺陷型B细胞或经7α，25-OHC预处理脱敏的正常B细胞​​显示归巢至脾滤泡区域减少。用CYP7B1抑制剂克霉唑阻断体内7α，25-OHC的合成，可降低小鼠脾脏中7α，25-OHC的含量并促进过继转移的预活化B细胞向T / B的迁移边界（脾滤泡中T区和B区之间的边界），模仿来自EBI2缺陷小鼠的预激活B细胞的表型。我们的研究结果表明，EBI2（一种控制B细胞迁移的孤儿G蛋白偶联受体）与某些氧固醇的已知免疫学作用之间存在意料之外的因果关系，从而揭示了此类分子的先前未知作用。

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  • 来源
    《Nature》 |2011年第7357期|p.519-523|共5页
  • 作者

    Changlu Liu; Xia V. Yang; Jiejun Wu; Chester Kuei; NeelakandhaS. Mani; Li Zhang; Jingxue Yu; Steven W. Sutton; NingQirn; Homayon Banie; Lars Karlsson; Siquan Sun; Timothy W. Lovenberg;

  • 作者单位

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

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

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

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

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

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

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

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

    Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA Roche R&D Center (China) Ltd., 720 Cai Lun Road, Building 5, Zhangjiang High-Tech Park, Pudong, Shanghai 201203, China;

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

    Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USARegulus Therapeutics, 3545 John Hopkins Court, San Diego, California 92121, USA;

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

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

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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