Oxidized Low-Density Lipoprotein (OxLDL)-Treated Dendritic Cells Promote Activation of T Cells in Human Atherosclerotic Plaque and Blood, Which Is Repressed by Statins: microRNA let-7c Is Integral to the Effect.
Oxidized Low-Density Lipoprotein (OxLDL)-Treated Dendritic Cells Promote Activation of T Cells in Human Atherosclerotic Plaque and Blood, Which Is Repressed by Statins: microRNA let-7c Is Integral to the Effect.
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氧化的低密度脂蛋白（OXLDL）处理的树突状细胞促进了人类动脉粥样硬化斑块和血液中T细胞的激活，这被汀类药物抑制：MicroRNA let-7c是该作用不可或缺的。
DOI：
10.1161/jaha.116.003976
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发表时间：
2016-09-20
影响因子：
5.4
通讯作者：
Liu A
中科院分区：
文献类型：
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作者：
Frostegård J;Zhang Y;Sun J;Yan K;Liu A
活化的 T 细胞和树突状细胞 (DC) 共定位于与斑块破裂相关的动脉粥样硬化斑块中。氧化低密度脂蛋白（oxLDL）促进免疫激活和炎症。我们研究了他汀类药物（阿托伐他汀和辛伐他汀）对人类 DC 成熟和 T 细胞激活的影响。人外周血单核细胞分化为 DC，并用 oxLDL 刺激。从接受颈动脉内膜切除术的患者或健康个体的颈动脉内膜切除术标本中分离出 T 细胞。幼稚 T 细胞与预处理的 DC 共培养。研究了他汀类药物的作用。 OxLDL 诱导 DC 成熟和 T 细胞激活。 OxLDL 诱导致动脉粥样硬化热休克蛋白 (HSP) 60 和 90，并降低潜在的动脉粥样硬化保护性热休克蛋白 27，阿托伐他汀可恢复其作用。暴露于 oxLDL 处理的 DC 中的 T 细胞产生干扰素-γ 和白细胞介素 (IL)-17。阿托伐他汀和辛伐他汀抑制 DC 成熟，降低 CD80、CD83 和 CD86 的表达，并限制肿瘤坏死因子-α、IL-1β 和 IL-6 的产生，并增加转化生长因子-β 和 IL-10 的分泌。他汀类药物处理的 DC 通过下调转录因子 T-bet 和 RORγt 表达来抑制 Th1 和/或 Th17 极化，并诱导 T 调节细胞产生 IL-10。 OxLDL 诱导的 miRNA let7c 以及 Akt 和 ERK 的磷酸化被他汀类药物抑制。 Let-7c 在 oxLDL 的介导作用中发挥着关键作用。对源自颈动脉粥样硬化斑块或健康个体的 T 细胞进行的实验也显示出类似的结果。他汀类药物可抑制 oxLDL 诱导的人 DC 成熟、限制 T 细胞活化、抑制致动脉粥样硬化的热休克蛋白谱并促进 T 调节细胞的诱导。 MicroRNA let-7c 是效果不可或缺的一部分。
Activated T cells and dendritic cells (DCs) are colocalized in atherosclerotic plaques in association with plaque rupture. Oxidized low‐density lipoprotein (oxLDL) promotes immune activation and inflammation. We studied the effects of statins (atorvastatin and simvastatin) on human DC maturation and T‐cell activation. Human peripheral blood monocytes were differentiated to DCs and stimulated with oxLDL. T cells were isolated from carotid endarterectomy specimens from patients undergoing carotid endarterectomy or from healthy individuals. Naïve T cells were cocultured with pretreated DCs. The effects of statin were studied. OxLDL induced DC maturation and T‐cell activation. OxLDL induced atherogenic heat shock proteins (HSP) 60 and 90 and decreased potentially atheroprotective heat shock protein 27, effects restored by atorvastatin. T cells exposed to oxLDL‐treated DCs produced interferon‐γ and interleukin (IL)‐17. Atorvastatin and simvastatin suppressed the DC maturation showing lower expression of CD80, CD83, and CD86, and limited their production of tumor necrosis factor‐α, IL‐1β and IL‐6, and increased transforming growth factor‐β and IL‐10 secretion. Statin‐treated DCs inhibited Th1 and/or Th17 polarization by downregulation of transcriptional factors T‐bet and RORγt expression, and induced T regulatory cells with IL‐10 production. OxLDL‐induced miRNA let7c and phosphorylation of Akt and ERK were repressed by statins. Let‐7c had a pivotal role in mediating effect of oxLDL. Experiments on T cells derived from carotid atherosclerotic plaques or healthy individuals showed similar results. Statins repress human DC maturation induced by oxLDL, limit T‐cell activation, and repress an atherogenic heat shock protein profile and promote induction of T regulatory cells. MicroRNA let‐7c is integral to the effects.