Down-regulation of DJ-1 Augments Neuroinflammation via Nrf2/Trx1/NLRP3 Axis in MPTP-induced Parkinson's Disease Mouse Model
Down-regulation of DJ-1 Augments Neuroinflammation via Nrf2/Trx1/NLRP3 Axis in MPTP-induced Parkinson's Disease Mouse Model
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DOI：
10.1016/j.neuroscience.2020.06.001
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发表时间：
2020-08-21
期刊：
影响因子：
3.3
通讯作者：
Ren, Xiang-Yang
中科院分区：
文献类型：
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作者：
Ji, Ya-Jie;Wang, Hui-Lin;Ren, Xiang-Yang
小胶质细胞介导的神经炎症在帕金森病（PD）的发病机制中起着重要作用。最近发现，PD 相关蛋白 DJ-1 的下调可增加小胶质细胞对脂多糖 (LPS) 的敏感性。然而，DJ-1 在小胶质细胞介导的 PD 神经炎症中的作用仍不清楚。采用1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）建立小鼠PD模型，并进行酪氨酸羟化酶（TH）染色来验证模型。采用腺病毒策略和shRNA分别敲低小鼠和BV2小胶质细胞中DJ-1的表达。 Western Blot和定量PCR检测细胞因子、DJ-1、Nrf2、Trx1和NRLP3的表达。使用免疫沉淀来检查 DJ-1 和 Nrf2 或 Trx1 之间的潜在相互作用。进行基于流式细胞术的膜联蛋白 V/7-AAD 测定来评估细胞凋亡。我们发现 DJ-1 的下调会加剧 PD 小鼠的神经炎症。 DJ-1 和 Nrf2 敲低促进 BV2 小胶质细胞的炎症和细胞凋亡，而 NLRP3 敲低则具有相反的作用。此外，DJ-1通过上调Nrf2/Trx1轴来调节NLRP3的表达。综上所述，这些数据表明 DJ-1 的下调通过 Nrf2/Trx1/NLRP3 轴加速了小胶质细胞介导的神经炎症和细胞凋亡。因此，我们的结果证明了 DJ-1 在 PD 发病机制中的重要作用，并有必要进一步研究 DJ-1 作为 PD 的治疗靶点。 (C) 2020 国际广播组织。由爱思唯尔有限公司出版。保留所有权利。
Microglia-mediated neuroinflammation plays a significant role in the pathogenesis of Parkinson's disease (PD). Down-regulation of DJ-1, a PD-associated protein, has been recently found to increase microglial sensitivity to lipopolysaccharides (LPS). However, the role of DJ-1 in microglia-mediated neuroinflammation in PD remains unclear. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to establish a PD model with mice and tyrosine hydroxylase (TH) staining was performed to validate the model. Adenovirus strategy and shRNA was employed to knockdown the expression of DJ-1 in mice and BV2 microglia, respectively. Western Blot and quantitative PCR were carried out to determine the expression of cytokines, DJ-1, Nrf2, Trx1 and NRLP3. Immunoprecipitation was used to examine the potential interaction between DJ-1 and Nrf2 or Trx1. Flow cytometry-based Annexin V/7-AAD assay were performed to evaluate cell apoptosis. We found that downregulation of DJ-1 exacerbated neuroinflammation in PD mice. DJ-1 and Nrf2 knockdown promoted inflammation and cell apoptosis in BV2 microglia, while NLRP3 knockdown had opposite effects. Furthermore, DJ-1 regulated the expression of NLRP3 by upregulating Nrf2/Trx1 axis. Taken together, these data suggested that downregulation of DJ-1 accelerated microglia-mediated neuroinflammation and cell apoptosis via Nrf2/Trx1/NLRP3 axis. Thus, our results demonstrated the important role of DJ-1 in PD pathogenesis and warranted further investigation of DJ-1 as a therapeutic target for PD. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.