MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis
MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis
复制标题
巨噬细胞代谢的微小RNA - 33依赖性调节在动脉粥样硬化中引导免疫细胞极化
DOI：
10.1172/jci81676
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发表时间：
2015-12-01
影响因子：
15.9
通讯作者：
Moore, Kathryn J.
中科院分区：
文献类型：
--
作者：
Ouimet, Mireille;Ediriweera, Hasini N.;Moore, Kathryn J.
细胞代谢越来越被认为是免疫细胞命运和功能的控制器。microRNA-33（miR-33）调节细胞脂质代谢并抑制参与胆固醇流出、HDL生物合成和脂肪酸氧化的基因。在这里，我们确定了miR-33介导的有氧糖酵解和线粒体氧化磷酸化平衡的破坏指示巨噬细胞炎症极化，并形成先天性和适应性免疫反应。巨噬细胞特异性Mir 33缺失增加了氧化呼吸，增强了备用呼吸能力，并诱导了M2巨噬细胞极化相关基因谱。此外，miR-33介导的M2极化需要miR-33靶向能量传感器AMP激活的蛋白激酶（AMPK），但不需要胆固醇流出。值得注意的是，在体外和小鼠模型中，miR-33抑制增加了视黄酸产生酶醛脱氢酶家族1、亚家族A2（ALDH 1A 2）的巨噬细胞表达和视网膜脱氢酶活性。与视黄酸促进诱导型T细胞增殖的能力一致，去除miR-33的巨噬细胞在初始CD 4（+）T细胞中诱导叉头盒P3（FOXP 3）表达的能力增强。最后，用miR-33抑制剂治疗高胆固醇血症小鼠8周，导致炎症抑制M2巨噬细胞和FOXP 3（+）T细胞在斑块中积累，并减少动脉粥样硬化进展。总的来说，这些结果揭示了miR-33调节巨噬细胞炎症，并证明miR-33拮抗作用部分地通过促进M2巨噬细胞极化和Treg诱导减少斑块炎症而具有动脉粥样硬化保护作用。
Cellular metabolism is increasingly recognized as a controller of immune cell fate and function. MicroRNA-33 (miR-33) regulates cellular lipid metabolism and represses genes involved in cholesterol efflux, HDL biogenesis, and fatty acid oxidation. Here, we determined that miR-33-mediated disruption of the balance of aerobic glycolysis and mitochondrial oxidative phosphorylation instructs macrophage inflammatory polarization and shapes innate and adaptive immune responses. Macrophage-specific Mir33 deletion increased oxidative respiration, enhanced spare respiratory capacity, and induced an M2 macrophage polarization-associated gene profile. Furthermore, miR-33-mediated M2 polarization required miR-33 targeting of the energy sensor AMP-activated protein kinase (AMPK), but not cholesterol efflux. Notably, miR-33 inhibition increased macrophage expression of the retinoic acid-producing enzyme aldehyde dehydrogenase family 1, subfamily A2 (ALDH1A2) and retinal dehydrogenase activity both in vitro and in a mouse model. Consistent with the ability of retinoic acid to foster inducible Tregs, miR-33-depleted macrophages had an enhanced capacity to induce forkhead box P3 (FOXP3) expression in naive CD4(+) T cells. Finally, treatment of hypercholesterolemic mice with miR-33 inhibitors for 8 weeks resulted in accumulation of inflammation-suppressing M2 macrophages and FOXP3(+)Tregs in plaques and reduced atherosclerosis progression. Collectively, these results reveal that miR-33 regulates macrophage inflammation and demonstrate that miR-33 antagonism is atheroprotective, in part, by reducing plaque inflammation by promoting M2 macrophage polarization and Treg induction.