BACKGROUND Brain innate immunity is vital for maintaining normal brain functions. Immune homeostatic imbalances play pivotal roles in the pathogenesis of neurological diseases including Parkinson's disease (PD). However, the molecular and cellular mechanisms underlying the regulation of brain innate immunity and their significance in PD pathogenesis are still largely unknown. METHODS Cre-inducible diphtheria toxin receptor (iDTR) and diphtheria toxin-mediated cell ablation was performed to investigate the impact of neuron-glial antigen 2 (NG2) glia on the brain innate immunity. RNA sequencing analysis was carried out to identify differentially expressed genes in mouse brain with ablated NG2 glia and lipopolysaccharide (LPS) challenge. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice were used to evaluate neuroinflammatory response in the presence or absence of NG2 glia. The survival of dopaminergic neurons or glial cell activation was evaluated by immunohistochemistry. Co-cultures of NG2 glia and microglia were used to examine the influence of NG2 glia to microglial activation. RESULTS We show that NG2 glia are required for the maintenance of immune homeostasis in the brain via transforming growth factor-β2 (TGF-β2)-TGF-β type II receptor (TGFBR2)-CX3C chemokine receptor 1 (CX3CR1) signaling, which suppresses the activation of microglia. We demonstrate that mice with ablated NG2 glia display a profound downregulation of the expression of microglia-specific signature genes and remarkable inflammatory response in the brain following exposure to endotoxin lipopolysaccharides. Gain- or loss-of-function studies show that NG2 glia-derived TGF-β2 and its receptor TGFBR2 in microglia are key regulators of the CX3CR1-modulated immune response. Furthermore, deficiency of NG2 glia contributes to neuroinflammation and nigral dopaminergic neuron loss in MPTP-induced mouse PD model. CONCLUSIONS These findings suggest that NG2 glia play a critical role in modulation of neuroinflammation and provide a compelling rationale for the development of new therapeutics for neurological disorders.

中文翻译：

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NG2胶质细胞通过TGF-β2/ TGFBR2轴调节大脑的先天免疫力。

背景技术脑固有的免疫力对于维持正常的脑功能至关重要。免疫稳态失衡在包括帕金森氏病（PD）在内的神经系统疾病的发病机理中起着关键作用。然而，大脑先天免疫调节的分子和细胞机制及其在PD发病机理中的意义仍是未知之数。方法进行Cre可诱导的白喉毒素受体（iDTR）和白喉毒素介导的细胞消融术，以研究神经胶质抗原2（NG2）胶质对大脑先天免疫的影响。进行了RNA测序分析，以鉴定消融的NG2胶质细胞和脂多糖（LPS）激发的小鼠脑中差异表达的基因。神经毒素1-甲基-4-苯基-1,2,3，用6-四氢吡啶（MPTP）处理的小鼠用于评估在存在或不存在NG2胶质细胞的情况下的神经炎症反应。通过免疫组织化学评估多巴胺能神经元或神经胶质细胞活化的存活。NG2胶质细胞和小胶质细胞的共培养用于检查NG2胶质细胞对小胶质细胞活化的影响。结果我们显示，NG2胶质细胞是通过转化生长因子-β2（TGF-β2）-TGF-βII型受体（TGFBR2）-CX3C趋化因子受体1（CX3CR1）信号传导来维持大脑中的免疫稳态所必需的小胶质细胞的激活。我们证明了与消融的NG2胶质细胞的小鼠在暴露于内毒素脂多糖后，对小胶质细胞特有的签名基因的表达和大脑中显着的炎症反应表现出深刻的下调。功能获得或丧失的研究表明，小胶质细胞中NG2胶质细胞衍生的TGF-β2及其受体TGFBR2是CX3CR1调节的免疫反应的关键调节剂。此外，在MPTP诱导的小鼠PD模型中，NG2胶质细胞缺乏导致神经炎症和黑质多巴胺能神经元丢失。结论这些发现表明NG2胶质细胞在神经炎症调节中起关键作用，并为开发新的神经系统疾病疗法提供了令人信服的理由。