Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Brain Behav Immun. 2020 Jul;87:543-555. doi: 10.1016/j.bbi.2020.01.026. Epub 2020 Feb 1.
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 CD3CD4 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.
中风是一种使人衰弱的疾病，在美国，它在 2017 年几乎占所有住院治疗的 20%，占所有死亡人数的 8%。在发生缺血性发作后，起源于脑微血管内皮细胞的炎症过程可以诱导受影响区域产生许多毒性作用，这些作用来自血脑屏障（BBB）的两侧。除了增加 BBB 的通透性外，受影响的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，并且还可以触发脑内小胶质细胞和星形胶质细胞的激活。我们已经确定了一种关键的 microRNA，即 let-7g，其水平在体内短暂性大脑中动脉闭塞（tMCAO）和体外氧葡萄糖剥夺（OGD）缺血/再灌注条件下分别急剧降低。我们观察到，let-7g*脂质体递送能够减轻中风后的炎症，降低 BBB 的通透性，限制 CD3CD4 T 细胞和 Ly6G 中性粒细胞对大脑的浸润，减轻小胶质细胞的激活和神经元死亡。这些影响随后改善了临床结果，表现为减轻中风后的步态不对称和肢体运动功能障碍。由于内皮细胞在传播中风和其他炎症的作用，因此需要能够减轻内皮炎症、限制缺血性损伤和改善中风后恢复的治疗方法。我们的研究结果表明，中枢神经系统炎症与免疫系统反应之间存在着重要的联系，并为未来的中风药物治疗奠定了重要的基础。
