MicroRNA-155 deficiency results in decreased macrophage inflammation and attenuated atherogenesis in apolipoprotein E-deficient mice.
MicroRNA-155 deficiency results in decreased macrophage inflammation and attenuated atherogenesis in apolipoprotein E-deficient mice.
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DOI：
10.1161/atvbaha.113.302701
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发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Fan D
中科院分区：
文献类型：
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作者：
Du F;Yu F;Wang Y;Hui Y;Carnevale K;Fu M;Lu H;Fan D
MicroRNA-155(MiR155)在免疫和巨噬细胞炎症中发挥重要作用。我们的目标是研究miR155在动脉粥样硬化形成中的作用。实时定量聚合酶链式反应显示miR155在小鼠和人动脉粥样硬化病变中均有表达。巨噬细胞miR155的表达与促炎细胞因子的表达呈正相关。慢病毒介导的miR155在巨噬细胞中的过表达通过靶向SOCS-1增强了巨噬细胞对内毒素的炎症反应，并抑制了乙酰化低密度脂蛋白负载的巨噬细胞的胆固醇外流，而miR155的缺乏则钝化了巨噬细胞的炎症反应，并可能通过促进脂质负载诱导的巨噬细胞自噬而增加了胆固醇的外流。接下来，我们研究了喂食西方饮食的apoE−/−和miR155−/−/apoE−/−(Dko)小鼠的动脉粥样硬化形成。与载脂蛋白E−/−小鼠相比，DKO小鼠主动脉根部动脉粥样硬化病变较轻，中性脂含量减少，巨噬细胞减少。流式细胞仪分析显示，DKO小鼠脾内调节性T细胞数量增加，Th17细胞和CD11b+/Ly6Chigh细胞数量减少。DKO小鼠的腹膜巨噬细胞在没有和存在内毒素刺激的情况下都显著减少了促炎细胞因子的表达和分泌。为了确定白细胞中的miR155是否与动脉粥样硬化有关，我们进行了骨髓移植研究。骨髓来源细胞中miR155的缺失抑制了载脂蛋白E−/−小鼠的动脉粥样硬化形成，表明造血细胞来源的miR155发挥了关键作用。MiR155缺陷通过减少巨噬细胞的炎症反应，增加巨噬细胞胆固醇的外流，并导致抗动脉粥样硬化的白细胞分布，从而减轻载脂蛋白E−/−小鼠的动脉粥样硬化形成。靶向miR155可能是阻止动脉粥样硬化形成的一个有前途的策略。
microRNA-155 (miR155) plays a critical role in immunity and macrophage inflammation. We aim to investigate the role of miR155 in atherogenesis. Quantitative real-time PCR showed that miR155 was expressed in mouse and human atherosclerotic lesions. miR155 expression in macrophages was positively correlated with proinflammatory cytokine expression. Lentivirus-mediated overexpression of miR155 in macrophages enhanced their inflammatory response to LPS through targeting SOCS-1, and impaired cholesterol efflux from acetylated LDL-loaded macrophages, whereas deficiency of miR155 blunted macrophage inflammatory responses, and enhanced cholesterol efflux possibly via enhancing lipid loading-induced macrophage autophagy. We next examined the atherogenesis in apoE−/− and miR155−/−/apoE−/− (DKO) mice fed a western diet. Compared with apoE−/− mice, the DKO mice developed less atherosclerosis lesion in aortic root, with reduced neutral lipid content and macrophages. Flow cytometric analysis showed that there were increased number of regulatory T cells, and reduced numbers of Th17 cells and CD11b+/Ly6Chigh cells in the spleen of DKO mice. Peritoneal macrophages from the DKO mice had significantly reduced pro-inflammatory cytokine expression and secretion both in the absence and presence of LPS stimulation. To determine whether miR155 in leukocytes contributes to atherosclerosis, we performed bone marrow transplantation study. Deficiency of miR155 in bone marrow-derived cells suppressed atherogenesis in apoE−/− mice, demonstrating that hematopoietic cell-derived miR155 plays a critical role. miR155 deficiency attenuates atherogenesis in apoE−/− mice by reducing inflammatory responses of macrophages, enhancing macrophage cholesterol efflux and resulting in an anti-atherogenic leukocyte profile. Targeting miR155 may be a promising strategy to halt atherogenesis.