Oxysterols direct B-cell migration through EBI2
Oxysterols direct B-cell migration through EBI2
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DOI：
10.1038/nature10226
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发表时间：
2011-07-28
期刊：
影响因子：
64.8
通讯作者：
Lovenberg, Timothy W.
中科院分区：
文献类型：
--
作者：
Liu, Changlu;Yang, Xia V.;Lovenberg, Timothy W.
EBI 2（也称为GPR 183）是一种孤儿G蛋白偶联受体，在脾脏中高度表达，并在EB病毒感染后上调（1）。最近的研究表明，这种受体控制滤泡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影响（7-9）。氧化固醇的生物学效应主要归功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氧固醇，并表明它们是EBI 2的内源性配体。最有效的配体和激活剂是7 α，25-二羟基胆固醇（OHC），EBI 2的解离常数为450 pM。在体外，7 α，25-OHC刺激EBI 2表达小鼠B和T细胞的迁移，半最大有效浓度值约为500 pM，但对EBI 2缺陷细胞没有影响。在体内，EBI 2缺陷型B细胞或通过7 α，25-OHC预处理脱敏的正常B细胞显示出归巢至脾脏滤泡区域的减少。用克霉唑（一种CYP 7 B1抑制剂）阻断体内7 α，25-OHC的合成，可降低小鼠脾脏中7 α，25-OHC的含量，并促进过继转移的预活化B细胞迁移至T/B边界（脾滤泡中T区和B区之间的边界），模拟EBI 2缺陷小鼠预活化B细胞的表型。我们的研究结果显示了EBI 2（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效应之间的意外因果关系，从而揭示了这类分子以前未知的作用。
EBI2 (also called GPR183) is an orphan G-protein-coupled receptor that is highly expressed in spleen and upregulated upon Epstein-Barr-virus infection(1). Recent studies indicated that this receptor controls follicular B-cell migration and T-cell-dependent antibody production(2-6). Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol metabolism(7-9). The biological effects of oxysterols have largely been credited to the activation of nuclear hormone receptors(10,11). Here we isolate oxysterols from porcine spleen extracts and show that they are endogenous ligands for EBI2. The most potent ligand and activator is 7 alpha,25-dihydroxycholesterol (OHC), with a dissociation constant of 450 pM for EBI2. In vitro, 7 alpha,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 7 alpha,25-OHC pre-treatment showed reduced homing to follicular areas of the spleen. Blocking the synthesis of 7 alpha,25-OHC in vivo with clotrimazole, a CYP7B1 inhibitor, reduced the content of 7 alpha,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.