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:NRSF^flox/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-1β, 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-1β 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.

神经炎症是帕金森氏病（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/阻遏因子1（RE1）-沉默转录因子（NRSF / REST）调节星形胶质细胞炎症过程中涉及的许多基因和信号途径。在本研究中，我们建立了GFAP-Cre：NRSF ^{flox / flox}条件敲除（cKO）小鼠。在1-甲基-4-苯基吡啶（MPP ⁺），LPS和LPS处理的BV-2小胶质细胞的条件培养基（CM）。还分析了暴露于MPP ⁺处理的原代星形胶质细胞条件培养基的BV-2小胶质细胞中的炎症分子表达。此外，使用亚甲基1-甲基-4-苯基-1、2、3、6-四氢吡啶盐酸盐（MPTP）方案建立小鼠PD模型，并在WT和cKO小鼠中全面评估了对黑质纹状体途径的损害。我们发现MPP ⁺诱导培养的星形胶质细胞中NRSF表达的显着增加。与野生型星形胶质细胞相比，炎症分子IL-1β，IL-6，COX-2和iNOS的表达LPS处理的BV-2细胞的CM挑战的NRSF缺陷星形胶质细胞中的Aβ急剧增加。与WT星形胶质细胞相比，在MPP ⁺处理的NRSF缺陷星形胶质细胞暴露于CM的BV-2小胶质细胞中，COX-2和IL-1β转录物显着升高。在cKO小鼠中，星形胶质细胞和小胶质细胞的激活更为明显，与MPTP给药后的野生型相比，黑纹状体多巴胺能系统受到的伤害更大。我们的研究结果表明与小胶质细胞精心编排的反应性NRSF缺陷型星形胶质细胞会加重PD的病理生理进程。