Endothelial cells suppress monocyte activation through secretion of extracellular vesicles containing antiinflammatory microRNAs
Endothelial cells suppress monocyte activation through secretion of extracellular vesicles containing antiinflammatory microRNAs
复制标题
DOI：
10.1182/blood-2014-11-611046
复制
发表时间：
2015-05-14
期刊：
影响因子：
20.3
通讯作者：
Fish, Jason E.
中科院分区：
文献类型：
--
作者：
Njock, Makon-Sebastien;Cheng, Henry S.;Fish, Jason E.
血液中含有高浓度的循环细胞外囊泡（EV），其水平和含量在包括心血管疾病在内的多种疾病状态下会发生变化。然而，循环EV的功能，特别是它们所包含的microRNA（miRNAs），知之甚少。我们试图确定由静止内皮细胞（EC）产生的分泌囊泡对单核细胞炎症反应的影响，并评估这些细胞之间是否发生microRNA的转移。我们观察到单核细胞与内皮细胞共培养（但不接触）对炎症激活是难治的。进一步的表征显示，内皮衍生的EV（EC-EV）通过增强免疫调节反应和减少促炎反应来抑制单核细胞活化。从小鼠血浆中分离的EV也抑制单核细胞活化。重要的是，体内注射EC-EV抑制了单核细胞/巨噬细胞活化，证实了我们的体外发现。我们发现，在EC-EV处理的单核细胞中，几种微RNA升高。特别是，miR-10 a从EC-EV转移到单核细胞，并可通过靶向NF-κ B途径的几种组分（包括IRAK 4）来抑制炎症信号传导。我们的研究结果表明，内皮细胞分泌的EV可以调节单核细胞活化，并表明EV分泌和/或microRNA含量的改变可能会影响心血管疾病背景下的血管炎症。
The blood contains high concentrations of circulating extracellular vesicles (EVs), and their levels and contents are altered in several disease states, including cardiovascular disease. However, the function of circulating EVs, especially the microRNAs (miRNAs) that they contain, are poorly understood. We sought to determine the effect of secreted vesicles produced by quiescent endothelial cells (ECs) on monocyte inflammatory responses and to assess whether transfer of microRNAs occurs between these cells. We observed that monocytic cells cocultured (but not in contact) with ECs were refractory to inflammatory activation. Further characterization revealed that endothelium-derived EVs (EC-EVs) suppressed monocyte activation by enhancing immunomodulatory responses and diminishing proinflammatory responses. EVs isolated from mouse plasma also suppressed monocyte activation. Importantly, injection of EC-EVs in vivo repressed monocyte/macrophage activation, confirming our in vitro findings. We found that several antiinflammatory microRNAs were elevated in EC-EV-treated monocytes. In particular, miR-10a was transferred to monocytic cells from EC-EVs and could repress inflammatory signaling through the targeting of several components of the NF-kappa B pathway, including IRAK4. Our findings reveal that ECs secrete EVs that can modulate monocyte activation and suggest that altered EV secretion and/or microRNA content may affect vascular inflammation in the setting of cardiovascular disease.