MicroRNA-124 regulates the expression of MEKK3 in the inflammatory pathogenesis of Parkinson's disease.
MicroRNA-124 regulates the expression of MEKK3 in the inflammatory pathogenesis of Parkinson's disease.
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MicroRNA-124 在帕金森病的炎症发病机制中调节 MEKK3 的表达。
DOI：
10.1186/s12974-018-1053-4
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发表时间：
2018-01-12
影响因子：
9.3
通讯作者：
Zhang S
中科院分区：
文献类型：
--
作者：
Yao L;Ye Y;Mao H;Lu F;He X;Lu G;Zhang S
帕金森病 (PD) 是最常见的神经退行性疾病，其特征是中脑多巴胺能 (DA) 神经元选择性丧失。中枢神经系统的慢性炎症由小胶质细胞介导，在帕金森病的病理进展中发挥着关键作用。在脂多糖 (LPS) 处理的 BV2 细胞和 PD 的 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 模型中，脑特异性 microRNA-124 (miR-124) 表达显着下调。然而，异常的 miR-124 表达是否可以调节小胶质细胞的激活仍知之甚少。通过暴露于 LPS 来激活 BV2 细胞，并分析 miR-124、丝裂原激活蛋白激酶激酶激酶 3 (MEKK3) 和 kappaB 核因子 (NF-κB) p-p65 的表达水平。进行 miR-124 的过表达和敲低研究，观察对 MEKK3/NF-κB 信号通路的影响，并评估促炎和神经毒性因子的诱导。此外，还进行了荧光素酶报告基因测定，以确认 MEKK3 是否是 miR-124 的直接靶标。同时，产生 miR-124、MEKK3 和 p-p65；中脑DA神经元死亡；在 MPTP 诱导的 PD 模型中，分析了使用或不使用 miR-124 治疗时小胶质细胞的激活情况。我们发现MEKK3的敲低可以通过调节NF-κB的表达来抑制小胶质细胞的活化。 miR-124的过表达可以有效减弱LPS诱导的促炎细胞因子的表达并促进神经保护因子的分泌。我们还首先确定了 miR-124 通过靶向 MEKK3/NF-κB 信号通路在介导小胶质细胞炎症反应中的独特作用。在小胶质细胞培养上清液 (MCS) 转移模型中，BV2 细胞中 miR-124 的过度表达或 MEKK3 的敲低可防止 SH-SY5Y 凋亡和死亡。此外，MEKK3 和 p-p65 在中脑中大量表达。此外，在 MPTP 诱导的 PD 模型中观察到它们的表达水平增加并且小胶质细胞活化。此外，外源性递送 miR-124 可以抑制 MEKK3 和 p-p65 的表达，并减弱 MPTP 治疗小鼠黑质致密部小胶质细胞的活化。在 MPTP 诱导的 PD 模型中，miR-124 还可以防止 MPTP 依赖性中脑 DA 细胞凋亡。综上所述，我们的数据表明 miR-124 可以通过调节 MEKK3/NF-κB 信号通路来抑制 PD 发展中的神经炎症，并暗示 miR-124 作为调节 PD 炎症反应的潜在治疗靶点。
Parkinson’s disease (PD) is the most prevalent neurodegenerative disorder that is characterised by selective loss of midbrain dopaminergic (DA) neurons. Chronic inflammation of the central nervous system is mediated by microglial cells and plays a critical role in the pathological progression of PD. Brain-specific microRNA-124 (miR-124) expression is significantly downregulated in lipopolysaccharide (LPS)-treated BV2 cells and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. However, whether abnormal miR-124 expression could regulate the activation of microglia remains poorly understood. BV2 cells were activated by exposure to LPS, and the expression levels of miR-124, mitogen-activated protein kinase kinase kinase 3 (MEKK3), and the nuclear factor of kappaB (NF-κB) p-p65 were analysed. Over-expression and knockdown studies of miR-124 were performed to observe the effects on MEKK3/NF-κB signalling pathways, and the induction of pro-inflammatory and neurotoxic factors was assessed. In addition, a luciferase reporter assay was conducted to confirm whether MEKK3 is a direct target of miR-124. Meanwhile, production of miR-124, MEKK3, and p-p65; midbrain DA neuronal death; or activation of microglia were analysed when treated with or without miR-124 in the MPTP-induced model of PD. We found that the knockdown of MEKK3 could inhibit the activation of microglia by regulating NF-κB expression. Over-expression of miR-124 could effectively attenuate the LPS-induced expression of pro-inflammatory cytokines and promote the secretion of neuroprotective factors. We also first identified a unique role of miR-124 in mediating the microglial inflammatory response by targeting MEKK3/NF-κB signalling pathways. In the microglial culture supernatant (MCS) transfer model, over-expression of the miR-124 or knockdown of MEKK3 in BV2 cells prevented SH-SY5Y from apoptosis and death. Moreover, MEKK3 and p-p65 were abundantly expressed in the midbrain. Furthermore, their expression levels increased and microglial activation was observed in the MPTP-induced model of PD. In addition, exogenous delivery of miR-124 could suppress MEKK3 and p-p65 expression and attenuate the activation of microglia in the substantia nigra pars compacta of MPTP-treated mice. miR-124 also could prevent MPTP-dependent apoptotic midbrain DA cell death in a MPTP-induced PD model. Taken together, our data suggest that miR-124 can inhibit neuroinflammation in the development of PD by regulating the MEKK3/NF-κB signalling pathways and implicate miR-124 as a potential therapeutic target for regulating the inflammatory response in PD.
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