The deficiency of NRSF/REST enhances the pro-inflammatory function of astrocytes in a model of Parkinson's disease
The deficiency of NRSF/REST enhances the pro-inflammatory function of astrocytes in a model of Parkinson's disease
复制标题
NRSF/REST 的缺乏增强了帕金森病模型中星形胶质细胞的促炎功能
DOI：
10.1016/j.bbadis.2019.165590
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发表时间：
2020-01-01
影响因子：
6.2
通讯作者：
Huang, Fang
中科院分区：
文献类型：
--
作者：
Li, Heng;Liu, Zhaolin;Huang, Fang
神经炎症是帕金森病(PD)的重要病理特征，主要由活化的星形胶质细胞和小胶质细胞介导。神经元限制性沉默因子/抑制因子1(Re1)沉默转录因子(NRSF/REST)调节许多参与星形胶质细胞炎症过程的基因和信号通路。在本研究中，我们建立了GFAP-CRE：NRSIflx/FLOX条件性基因敲除(CKO)小鼠。用1-甲基-4-苯基吡啶(MPP+)、脂多糖(LPS)和内毒素处理的BV-2小胶质细胞条件培养液(CM)刺激野生型(WT)和CKO小鼠原代星形胶质细胞，检测炎症相关分子的表达。分析MPP+处理的原代星形胶质细胞条件培养液对BV-2小胶质细胞炎性分子表达的影响。采用亚急性方案1-甲基-4-苯基-1，2，3，6-四氢吡啶盐酸盐(MPTP)建立小鼠帕金森病模型，综合评价MPTP对WT和CKO小鼠黑质纹状体通路的损害。我们发现MPP+诱导培养的星形胶质细胞NRSF表达显著增加。与WT星形胶质细胞相比，在NRSF缺陷的星形胶质细胞中，炎症分子IL-1β、IL-6、COX-2和iNOS的表达显著增加。与WT星形胶质细胞相比，经MPP+处理的NRSF缺陷星形胶质细胞暴露于CM后，BV-2小胶质细胞中COX-2和IL-1β的转录水平显著升高。CKO小鼠给予MPTP后，星形胶质细胞和小胶质细胞的激活更加明显，黑质纹状体多巴胺能系统的损伤比WT小鼠更严重。我们的结果表明，反应性NRSF缺乏的星形胶质细胞与小胶质细胞协调，加剧了帕金森病的病理生理进展。
Neuroinflammation, as an important pathological characteristic of Parkinson's disease (PD), is primarily mediated by activated astrocytes and microglia. Neuron-restrictive silencer factor/repressor element 1 (RE1)-silencing transcription factor (NRSF/REST) regulates many genes and signal pathways involved in the inflammatory process in astrocytes. In the present study, we established the GFAP-Cre:NRSIflox/flox conditional knockout (cKO) mice. The expression of inflammation-associated molecules were measured in primary astrocytes from wild type (WT) and cKO mice after stimulation by 1-Methyl-4-phenylpyridine (MPP+), LPS, and conditioned medium (CM) of LPS-treated BV-2 microglial cells. The inflammatory molecule expression in BV-2 microglial cells exposed to conditioned medium of MPP+-treated primary astrocytes were also analyzed. Moreover, a subacute regimen of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride (MPTP) was used to establish mouse PD model and the damages to the nigrostriatal pathway were comprehensively evaluated in WT and cKO mice. We found that MPP+ induced a remarkable increase of NRSF expression in cultured astrocytes. Compared to WT astrocytes, the expression of inflammatory molecules IL-1 beta, IL-6, COX-2, and iNOS increased dramatically in NRSF deficient astrocytes challenged with CM of LPS-treated BV-2 cells. COX-2 and IL-1 beta transcripts were significantly elevated in BV-2 microglial cells exposed to CM of MPP+-treated NRSF deficient astrocytes compared to WT astrocytes. In cKO mice, the activation of astrocytes and microglial cells was more obvious, and the nigrostriatal dopaminergic system was more heavily injured compared to their WT counterparts after MPTP administration. Our results suggest that reactive NRSF deficient astrocytes orchestrated with microglial cells aggravate the pathophysiological progress in PD.