MicroRNA Cargo of Extracellular Vesicles from Alcohol-exposed Monocytes Signals Naive Monocytes to Differentiate into M2 Macrophages
MicroRNA Cargo of Extracellular Vesicles from Alcohol-exposed Monocytes Signals Naive Monocytes to Differentiate into M2 Macrophages
复制标题
酒精暴露的单核细胞所释放细胞外囊泡中的微小核糖核酸（miRNA），可向未受刺激的单核细胞发出信号，促使其分化为M2型巨噬细胞。
DOI：
10.1074/jbc.m115.694133
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发表时间：
2016-01-01
影响因子：
4.8
通讯作者：
Szabo, Gyongyi
中科院分区：
文献类型：
--
作者：
Saha, Banishree;Momen-Heravi, Fatemeh;Szabo, Gyongyi
细胞释放的膜包被的细胞外囊泡（EV）可以作为生物材料和信号传递的载体。最近，我们证明酒精处理的肝细胞通过含有 microRNA (miRNA) 的外泌体与免疫细胞进行交互。在这里，我们假设暴露于酒精的单核细胞可以通过 EV 与幼稚单核细胞进行交流。我们观察到，在酒精存在下，原代人单核细胞和 THP-1 单核细胞分泌的 EV（主要是外泌体）数量增加，且呈浓度和时间依赖性。来自酒精处理的单核细胞的 EV 刺激初始单核细胞极化为 M2 巨噬细胞，表现为 CD68（巨噬细胞标记物）、M2 标记物（CD206（甘露糖受体）和 CD163（清道夫受体））表面表达增加、IL-10 和 TGF 分泌以及吞噬细胞活性增加。来自酒精处理的 THP-1 单核细胞的 EV 的 miRNA 分析揭示了 M2 极化 miRNA miR-27a 的高表达。用过表达 miR-27a 的对照 EV 处理幼稚单核细胞，重现了酒精处理单核细胞的 EV 对幼稚单核细胞的影响，并诱导 M2 极化，表明酒精 EV 的作用是由 miR-27a 介导的。我们发现 miR-27a 通过靶向单核细胞上的 CD206 表达来调节吞噬过程。重要的是，对酒精性肝炎患者血浆中循环 EV 的分析显示，与健康对照相比，含有高水平 miR-27a 的 EV 数量有所增加。我们的结果表明：首先，酒精会增加单核细胞中 EV 的产生；其次，暴露于酒精的单核细胞通过 EV 与幼稚单核细胞进行通信；第三，单核细胞来源的 EV 中的 miR-27a 可以将初始单核细胞编程为极化为 M2 巨噬细胞。
Membrane-coated extracellular vesicles (EVs) released by cells can serve as vehicles for delivery of biological materials and signals. Recently, we demonstrated that alcohol-treated hepatocytes cross-talk with immune cells via exosomes containing microRNA (miRNAs). Here, we hypothesized that alcohol-exposed monocytes can communicate with naive monocytes via EVs. We observed increased numbers of EVs, mostly exosomes, secreted by primary human monocytes and THP-1 monocytic cells in the presence of alcohol in a concentration- and time-dependent manner. EVs derived from alcohol-treated monocytes stimulated naive monocytes to polarize into M2 macrophages as indicated by increased surface expression of CD68 (macrophage marker), M2 markers (CD206 (mannose receptor) and CD163 (scavenger receptor)), secretion of IL-10, and TGF and increased phagocytic activity. miRNA profiling of the EVs derived from alcohol-treated THP-1 monocytes revealed high expression of the M2-polarizing miRNA, miR-27a. Treatment of naive monocytes with control EVs overexpressing miR-27a reproduced the effect of EVs from alcohol-treated monocytes on naive monocytes and induced M2 polarization, suggesting that the effect of alcohol EVs was mediated by miR-27a. We found that miR-27a modulated the process of phagocytosis by targeting CD206 expression on monocytes. Importantly, analysis of circulating EVs from plasma of alcoholic hepatitis patients revealed increased numbers of EVs that contained high levels of miR-27a as compared with healthy controls. Our results demonstrate the following: first, alcohol increases EV production in monocytes; second, alcohol-exposed monocytes communicate with naive monocytes via EVs; and third, miR-27a cargo in monocyte-derived EVs can program naive monocytes to polarize into M2 macrophages.