Apolipoprotein E enhances microRNA-146a in monocytes and macrophages to suppress nuclear factor-κB-driven inflammation and atherosclerosis.
Apolipoprotein E enhances microRNA-146a in monocytes and macrophages to suppress nuclear factor-κB-driven inflammation and atherosclerosis.
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DOI：
10.1161/circresaha.117.305844
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发表时间：
2015-06-19
影响因子：
20.1
通讯作者：
Raffai RL
中科院分区：
文献类型：
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作者：
Li K;Ching D;Luk FS;Raffai RL
载脂蛋白E(ApoE)具有抗炎作用，可预防动脉粥样硬化和其他炎症性疾病。然而，载脂蛋白E抑制通常与动脉粥样硬化相关的白细胞的细胞激活的机制仍不完全清楚。为了验证载脂蛋白E通过调节这些白细胞中的细胞microRNA水平来抑制炎症和动脉粥样硬化的假设。对野生型小鼠这些白细胞亚群中载脂蛋白E表达的评估表明，只有巨噬细胞和单核细胞大量表达载脂蛋白E。巨噬细胞和单核细胞不表达载脂蛋白E导致核因子-κB(NF-κB)信号增强，并在内毒素刺激下产生过度炎症反应。这与核因子-κB信号的关键负调控因子MicroRNA-146a水平降低有关。载脂蛋白E在−/−巨噬细胞和单核细胞中的异位表达使miR-146a水平升高，而在野生型细胞中的沉默作用则相反。机制上，apoE上调转录因子PU.1的表达，从而上调pri-miR-146的转录水平，表明apoE对miR-146a具有转录调控作用。在体内，即使在低形态apoE小鼠的巨噬细胞和单核细胞中表达少量apoE也会导致miR-146a水平升高，并在高脂血症环境下抑制巨噬细胞促炎反应、Ly-6 Chigh单核细胞增殖和动脉粥样硬化。因此，通过系统地在APOE−/−LDLR−/−和LDLR−/−小鼠中传递miR-146a模拟物，miR-146a的细胞浓缩可以在没有降低血脂的情况下减轻单核/巨噬细胞的激活和动脉粥样硬化。我们的数据表明，细胞内载脂蛋白E的表达通过增加单核细胞和巨噬细胞中miR-146a的水平来抑制NF-κB介导的炎症和动脉粥样硬化。
Apolipoprotein E (apoE) exerts anti-inflammatory properties that protect against atherosclerosis and other inflammatory diseases. However, mechanisms by which apoE suppresses the cellular activation of leukocytes commonly associated with atherosclerosis remain incompletely understood. To test the hypothesis that apoE suppresses inflammation and atherosclerosis by regulating cellular microRNA levels in these leukocytes. An assessment of apoE expression among such leukocyte subsets in wild-type mice revealed that only macrophages and monocytes express apoE abundantly. An absence of apoE expression in macrophages and monocytes resulted in enhanced nuclear factor-κB (NF-κB) signaling and an exaggerated inflammatory response upon stimulation with lipopolysaccharide. This correlated with reduced levels of microRNA-146a, a critical negative regulator of NF-κB signaling. Ectopic apoE expression in Apoe−/− macrophages and monocytes raised miR-146a levels, while its silencing in wild-type cells had an opposite effect. Mechanistically, apoE increased the expression of transcription factor PU.1, which raised levels of pri-miR-146 transcripts, demonstrating that apoE exerts transcriptional control over miR-146a. In vivo, even a small amount of apoE expression in macrophages and monocytes of hypomorphic apoE mice led to increased miR-146a levels, and inhibited macrophage pro-inflammatory responses, Ly-6Chigh monocytosis, and atherosclerosis in the settings of hyperlipidemia. Accordingly, cellular enrichment of miR-146a through the systemic delivery of miR-146a mimetics in Apoe−/−Ldlr−/− and Ldlr−/− mice attenuated monocyte/macrophage activation and atherosclerosis in the absence of plasma lipid reduction. Our data demonstrate that cellular apoE expression suppresses NF-κB–mediated inflammation and atherosclerosis by enhancing miR-146a levels in monocytes and macrophages.