Extracellular miR-146a-5p Induces Cardiac Innate Immune Response and Cardiomyocyte Dysfunction.
Extracellular miR-146a-5p Induces Cardiac Innate Immune Response and Cardiomyocyte Dysfunction.
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DOI：
10.4049/immunohorizons.2000075
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发表时间：
2020-09-21
期刊：
影响因子：
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通讯作者：
Chao W
中科院分区：
文献类型：
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作者：
Shimada BK;Yang Y;Zhu J;Wang S;Suen A;Kronstadt SM;Jeyaram A;Jay SM;Zou L;Chao W
先前的研究已经证明，短暂的心肌缺血导致细胞核酸如RNA的释放。据报道，细胞外RNA在动物心肌炎症和缺血性损伤中起关键作用。RNA分析已经确定，许多microRNA（miRNAs），如ss-miR-146 a-5 p，在心肌缺血后在血浆中上调，并且某些富含尿苷的miRNAs通过ssRNA传感机制在免疫细胞中表现出强烈的促炎作用。然而，细胞外miRNAs对心肌炎症和心脏细胞功能的影响仍然未知。在这项研究中，我们用装载在细胞外囊泡中的miR-146 a-5 p处理成年小鼠心肌细胞，观察到CXCL-2、IL-6和TNF-α的剂量依赖性和TLR 7依赖性产生。在体内，单剂量心肌注射miR-146 a-5 p诱导细胞因子表达（CXCL 2、IL-6和TNF-α）和先天免疫细胞活化（CD 45+白细胞、Ly 6Cmid+单核细胞、Ly 6 G+中性粒细胞），这在TLR 7 KO小鼠的心脏中显著减弱。我们发现，来自miR-146 a处理的巨噬细胞的条件培养基刺激了成年心肌细胞中促炎细胞因子的产生，并显著抑制了它们的肌节缩短。最后，使用电细胞阻抗传感测定，我们发现来自miR-146 a处理的心脏成纤维细胞或心肌细胞的条件培养基损害冠状动脉内皮细胞的屏障功能。综上所述，这些数据表明，细胞外miR-146 a-5 p通过细胞间相互作用和先天免疫TLR 7核酸传感激活多种心脏细胞并诱导心肌炎症和心肌细胞功能障碍。
Previous studies have demonstrated that transient myocardial ischemia leads to release of cellular nucleic acids such as RNA. Extracellular RNA reportedly plays a pivotal role in myocardial inflammation and ischemic injury in animals. RNA profiling has identified that numerous microRNA (miRNAs), such as ss-miR-146a-5p, are upregulated in plasma following myocardial ischemia, and certain uridine-rich miRNAs exhibit strong proinflammatory effects in immune cells via ssRNA-sensing mechanism. However, the effect of extracellular miRNAs on myocardial inflammation and cardiac cell function remains unknown. In this study, we treated adult mouse cardiomyocytes with miR-146a-5p loaded in extracellular vesicles and observed a dose- and TLR7-dependent production of CXCL-2, IL-6, and TNF-α. In vivo, a single dose of myocardial injection of miR-146a-5p induced both cytokine expression (CXCL2, IL-6, and TNF-α) and innate immune cell activation (CD45+ leukocytes, Ly6Cmid+ monocytes, Ly6G+ neutrophils), which was significantly attenuated in the hearts of TLR7 KO mice. We discovered that conditioned media from miR-146a-treated macrophages stimulated proinflammatory cytokine production in adult cardiomyocytes and significantly inhibited their sarcomere shortening. Finally, using an electric cell impedance-sensing assay, we found that the conditioned media from miR-146a-treated cardiac fibroblasts or cardiomyocytes impaired the barrier function of coronary artery endothelial cells. Taken together, these data demonstrate that extracellular miR-146a-5p activates multiple cardiac cells and induces myocardial inflammation and cardiomyocyte dysfunction via intercellular interaction and innate immune TLR7 nucleic acid sensing.