Hypercholesterolemia promotes bone marrow cell mobilization by perturbing the SDF-1:CXCR4 axis
Hypercholesterolemia promotes bone marrow cell mobilization by perturbing the SDF-1:CXCR4 axis
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DOI：
10.1182/blood-2009-08-240580
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发表时间：
2010-05-13
期刊：
影响因子：
20.3
通讯作者：
Dias, Sergio
中科院分区：
文献类型：
--
作者：
Gomes, Ana L.;Carvalho, Tania;Dias, Sergio
高胆固醇血症与外周血白细胞升高和血小板水平升高有关，通常归因于胆固醇诱导的促炎细胞因子。骨髓(BM)细胞动员和血小板生成是通过破坏SDF-1：CXCR4轴实现的，即用粒细胞集落刺激因子和/或CXCR4拮抗剂。在这里，我们显示高胆固醇扰乱骨髓SDF-1：CXCR4轴；促进B细胞、中性粒细胞和祖细胞(HPC)的动员；并产生血小板增多。在30天的高胆固醇喂养试验后，出现高胆固醇血症，导致低密度脂蛋白胆固醇水平升高，低密度脂蛋白胆固醇与高密度脂蛋白胆固醇比率倒置。高胆固醇血症小鼠表现为淋巴细胞增多，中性粒细胞、造血祖细胞和血小板增多，并伴有血统特异性的骨髓减少。组织学分析显示，巨核细胞的数量保持不变，但在高胆固醇小鼠中，它们形成了与骨髓血管接触的大簇。在体外，低密度脂蛋白诱导基质细胞衍生因子-1(SDF-1)的产生，这表明巨核细胞的去局部化是SDF-1梯度改变的结果。低密度脂蛋白还能刺激B细胞和HPC向SDF-1迁移，这种迁移可被清道夫受体BI型(胆固醇受体)抑制所阻断。相应地，高胆固醇血症小鼠外周血SDF-1水平升高，血小板、CXCR4阳性B淋巴细胞、中性粒细胞和HPC增加。高胆固醇干扰骨髓SDF-1：CXCR4轴，导致淋巴细胞增多、血小板增多和HPC动员。(血。2010；115(19)：3886-3894)
Hypercholesterolemia is associated with elevated peripheral blood leukocytes and increased platelet levels, generally attributed to cholesterol-induced proinflammatory cytokines. Bone marrow (BM) cell mobilization and platelet production is achieved by disrupting the SDF-1:CXCR4 axis, namely with granulocyte colony-stimulating factor and/or CXCR4 antagonists. Here we show that high cholesterol disrupts the BM SDF-1:CXCR4 axis; promotes the mobilization of B cells, neutrophils, and progenitor cells (HPCs); and creates thrombocytosis. Hypercholesterolemia was achieved after a 30-day high-cholesterol feeding trial, resulting in elevated low-density lipoprotein (LDL) cholesterol levels and inversion of the LDL to high-density lipoprotein cholesterol ratio. Hypercholesterolemic mice displayed lymphocytosis, increased neutrophils, HPCs, and thrombocytosis with a lineage-specific decrease in the BM. Histologic analysis revealed that megakaryocyte numbers remained unaltered but, in high-cholesterol mice, they formed large clusters in contact with BM vessels. In vitro, LDL induced stromal cell-derived factor-1 (SDF-1) production, suggesting that megakaryocyte delocalization resulted from an altered SDF-1 gradient. LDL also stimulated B cells and HPC migration toward SDF-1, which was blocked by scavenger receptor class B type I (cholesterol receptor) inhibition. Accordingly, hypercholesterolemic mice had increased peripheral blood SDF-1 levels, increased platelets, CXCR4-positive B lymphocytes, neutrophils, and HPCs. High cholesterol interferes with the BM SDF-1:CXCR4 axis, resulting in lymphocytosis, thrombocytosis, and HPC mobilization. (Blood. 2010; 115(19):3886-3894)