CX3CL1/CX3CR1 axis attenuates early brain injury via promoting the delivery of exosomal microRNA-124 from neuron to microglia after subarachnoid hemorrhage
CX3CL1/CX3CR1 axis attenuates early brain injury via promoting the delivery of exosomal microRNA-124 from neuron to microglia after subarachnoid hemorrhage
复制标题
CX3CL1/CX3CR1轴通过促进蛛网膜下腔出血后外泌体microRNA-124从神经元向小胶质细胞的递送来减轻早期脑损伤
DOI：
10.1186/s12974-020-01882-6
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发表时间：
2020-07-14
影响因子：
9.3
通讯作者：
Chen, Gang
中科院分区：
文献类型：
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作者：
Chen, Xiao;Jiang, Ming;Chen, Gang
小胶质细胞激活介导的神经炎症是蛛网膜下腔出血（SAH）后早期脑损伤（EBI）的主要原因。microRNA-124（miR-124）是中枢神经系统（CNS）中含量最丰富的miRNAs，通过靶向CCAAT增强子结合蛋白α（C/EBPα）在小胶质细胞活化中发挥重要作用。方法采用自体动脉血注入视交叉前池建立大鼠SAH模型，将培养的原代神经元和小胶质细胞暴露于氧合血红蛋白中模拟SAH。结果SAH患者脑组织中CX 3CL 1和CX 3CR 1表达明显降低。我们还观察到大鼠SAH后神经元中CX 3CL 1和小胶质细胞中CX 3CR 1的水平降低。此外，SAH后小胶质细胞表现出巨噬细胞样形态和高水平的CD 45和主要组织相容性复合物（MHC）II类的活化表型。CX 3CL 1/CX 3CR 1过表达后，CD 45和MHC Ⅱ类分子水平以及炎症因子肿瘤坏死因子α、白细胞介素1α和补体1 q的释放均显著降低。SAH后神经元变性和行为功能障碍也增加，CX 3CL 1/CX 3CR 1过表达抑制了这两种情况。此外，我们发现SAH后，从神经元到小胶质细胞的外泌体miR-124的递送显著减少，伴随着C/EBPα表达的增加，并且被CX 3CL 1/CX 3CR 1过表达抑制。结论CX 3CL 1/CX 3CR 1轴可能通过促进exosomal miR-124向小胶质细胞的转运，抑制小胶质细胞的活化和炎症反应，从而发挥对SAH后EBI的保护作用。
BackgroundMicroglial activation-mediated neuroinflammation is a major contributor to early brain injury (EBI) after subarachnoid hemorrhage (SAH). MicroRNA-124 (miR-124) is the most abundant miRNAs in the central nervous system (CNS) and plays a vital role in microglial activation by targeting protein CCAAT-enhancer-binding protein α (C/EBPα). It has been reported that the CX3CL1/CX3CR1 axis is involved in the delivery of miR-124 from neurons to microglia.MethodsAn experimental rat SAH model was established by injecting autologous arterial blood into the prechiasmatic cistern, and cultured primary neurons and microglia were exposed to oxyhemoglobin to mimic SAH in vitro. We additionally exploited specific expression plasmids encoding CX3CL1 and CX3CR1.ResultsWe observed significant decreases in CX3CL1 and CX3CR1 in the brain tissues of SAH patients. We also observed decreases in the levels of CX3CL1 in neurons and CX3CR1 in microglia after SAH in rats. Moreover, microglia exhibited an activated phenotype with macrophage-like morphology and high levels of CD45 and major histocompatibility complex (MHC) class II after SAH. After overexpression of CX3CL1/CX3CR1, the level of CD45 and MHC class II and the release of inflammatory factors tumor necrosis factor α, interleukin 1α and complement 1q were significantly decreased. There was also increased neuronal degeneration and behavior dysfunction after SAH, both of which were inhibited by CX3CL1/CX3CR1 overexpression. Additionally, we found that the delivery of exosomal miR-124 from neurons to microglia was significantly reduced after SAH, accompanied by an increase in C/EBPα expression, and was inhibited by CX3CL1/CX3CR1 overexpression. In conclusion, the CX3CL1/CX3CR1 axis may play protective roles after SAH by promoting the delivery of exosomal miR-124 to microglia and attenuate microglial activation and neuroinflammation.ConclusionsCX3CL1/CX3CR1 axis may be a potential intervention target for the inhibition of SAH-induced EBI by promoting exosome transport of miR-124 to microglia.