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首页> 外文期刊>Journal of neuroinflammation >The microRNA miR-181c controls microglia-mediated neuronal apoptosis by suppressing tumor necrosis factor
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The microRNA miR-181c controls microglia-mediated neuronal apoptosis by suppressing tumor necrosis factor

机译：microRNA miR-181c通过抑制肿瘤坏死因子控制小胶质细胞介导的神经元凋亡

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Background Post-ischemic microglial activation may contribute to neuronal damage through the release of large amounts of pro-inflammatory cytokines and neurotoxic factors. The involvement of microRNAs (miRNAs) in the pathogenesis of disorders related to the brain and central nervous system has been previously studied, but it remains unknown whether the production of pro-inflammatory cytokines is regulated by miRNAs. Methods BV-2 and primary rat microglial cells were activated by exposure to oxygen-glucose deprivation (OGD). Global cerebral ischemia was induced using the four-vessel occlusion (4-VO) model in rats. Induction of pro-inflammatory and neurotoxic factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and nitric oxide (NO), were assessed by ELISA, immunofluorescence, and the Griess assay, respectively. The miRNA expression profiles of OGD-activated BV-2 cells were subsequently compared with the profiles of resting cells in a miRNA microarray. BV-2 and primary rat microglial cells were transfected with miR-181c to evaluate its effects on TNF-α production after OGD. In addition, a luciferase reporter assay was conducted to confirm whether TNF-α is a direct target of miR-181c. Results OGD induced BV-2 microglial activation in vitro, as indicated by the overproduction of TNF-α, IL-1β, and NO. Global cerebral ischemia/reperfusion injury induced microglial activation and the release of pro-inflammatory cytokines in the hippocampus. OGD also downregulated miR-181c expression and upregulated TNF-α expression. Overproduction of TNF-α after OGD-induced microglial activation provoked neuronal apoptosis, whereas the ectopic expression of miR-181c partially protected neurons from cell death caused by OGD-activated microglia. RNAinterference-mediated knockdown of TNF-α phenocopied the effect of miR-181c-mediated neuronal protection, whereas overexpression of TNF-α blocked the miR-181c-dependent suppression of apoptosis. Further studies showed that miR-181c could directly target the 3′-untranslated region of TNF-α mRNA, suppressing its mRNA and protein expression. Conclusions Our data suggest a potential role for miR-181c in the regulation of TNF-α expression after ischemia/hypoxia and microglia-mediated neuronal injury.
机译：背景缺血后小胶质细胞活化可能通过释放大量促炎性细胞因子和神经毒性因子而导致神经元损伤。先前已经研究了microRNA（miRNA）在与脑和中枢神经系统有关的疾病的发病机理中的作用，但是促炎性细胞因子的产生是否受miRNA调节尚不清楚。方法通过暴露于氧葡萄糖剥夺（OGD）激活BV-2和原代大鼠小胶质细胞。使用四血管闭塞（4-VO）模型在大鼠中诱发全脑缺血。分别通过ELISA，免疫荧光和Griess分析评估促炎和神经毒性因子（如肿瘤坏死因子（TNF）-α，白介素（IL）-1β和一氧化氮（NO））的诱导。随后将OGD激活的BV-2细胞的miRNA表达谱与miRNA微阵列中静止细胞的谱进行比较。用miR-181c转染BV-2和原代大鼠小胶质细胞，以评估其对OGD后对TNF-α产生的影响。另外，进行荧光素酶报告基因测定以确认TNF-α是否是miR-181c的直接靶标。结果OGD体外诱导BV-2小胶质细胞活化，这由TNF-α，IL-1β和NO的过量产生所表明。全脑缺血/再灌注损伤诱导海马小胶质细胞活化和促炎细胞因子的释放。 OGD还下调了miR-181c表达并上调了TNF-α表达。 OGD诱导的小胶质细胞活化后，TNF-α的过量产生引起神经元凋亡，而miR-181c的异位表达部分保护了神经元免受OGD活化的小胶质细胞引起的细胞死亡。 RNA干扰介导的TNF-α的敲除显露了miR-181c介导的神经元保护的作用，而TNF-α的过表达阻止了miR-181c依赖性的凋亡抑制。进一步的研究表明，miR-181c可以直接靶向TNF-αmRNA的3'-非翻译区，从而抑制其mRNA和蛋白质表达。结论我们的数据表明miR-181c在缺血/缺氧和小胶质细胞介导的神经元损伤后，在调节TNF-α表达中具有潜在作用。

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