Stroke is a debilitating disease, accounting for almost 20% of all hospital visits, and 8% of all fatalities in the United States in 2017. Following an ischemic attack, inflammatory processes originating from endothelial cells within the brain microvasculature can induce many toxic effects into the impacted area, from both sides of the blood brain barrier (BBB). In addition to increased BBB permeability, impacted brain microvascular endothelial cells can recruit macrophages and other immune cells from the periphery and can also trigger the activation of microglia and astrocytes within the brain. We have identified a key microRNA, let-7g, which levels were drastically diminished as consequence of transient middle cerebral artery occlusion(tMCAO) in vivo and oxygen-glucose deprivation (OGD) in vitro ischemia/reperfusion conditions, respectively. We have observed that let-7g* liposome-based delivery is capable of attenuating inflammation after stroke, reducing BBB permeability, limiting brain infiltration by CD3+CD4+ T-cells and Ly6G+ neutrophils, lessening microglia activation and neuronal death. These effects consequently improved clinical outcomes, shown by mitigating post-stroke gait asymmetry and extremity motor function. Due to the role of the endothelium in propagating the effects of stroke and other inflammation, treatments which can reduce endothelial inflammation and limit ischemic damage and improving recovery after a stroke are required. Our findings demonstrate a critical link between the CNS inflammation and the immune system reaction and lay important groundwork for future stroke pharmacotherapies.

中文翻译：

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let-7g 对抗小鼠缺血/再灌注中风模型中的内皮功能障碍并改善神经功能


中风是一种使人衰弱的疾病，2017 年，中风占美国所有就诊人数的近 20%，占所有死亡人数的 8%。缺血性发作后，源自大脑微脉管系统内皮细胞的炎症过程可诱发许多毒性作用血脑屏障 (BBB) 两侧的受影响区域。除了血脑屏障通透性增加之外，受影响的大脑微血管内皮细胞还可以从外周招募巨噬细胞和其他免疫细胞，还可以触发大脑内小胶质细胞和星形胶质细胞的激活。我们已经鉴定出一种关键的 microRNA，let-7g，其水平分别由于体内短暂性大脑中动脉闭塞（tMCAO）和体外缺血/再灌注条件下氧糖剥夺（OGD）而急剧下降。我们观察到，let-7g* 基于脂质体的递送能够减轻中风后的炎症，降低 BBB 通透性，限制 CD3+CD4+ T 细胞和 Ly6G+ 中性粒细胞的脑浸润，减少小胶质细胞激活和神经元死亡。这些效果因此改善了临床结果，通过减轻中风后步态不对称和四肢运动功能来证明。由于内皮在传播中风和其他炎症影响中的作用，需要能够减少内皮炎症、限制缺血性损伤并改善中风后恢复的治疗。我们的研究结果证明了中枢神经系统炎症和免疫系统反应之间的关键联系，并为未来中风药物治疗奠定了重要基础。