NG2 glia regulate brain innate immunity via TGF-β2/TGFBR2 axis
NG2 glia regulate brain innate immunity via TGF-β2/TGFBR2 axis
复制标题
NG2胶质细胞通过TGF-β2/TGFBR2轴调节大脑先天免疫
DOI：
10.1186/s12916-019-1439-x
复制
发表时间：
2019-11-15
期刊：
影响因子：
9.3
通讯作者：
Zhou, Jia-wei
中科院分区：
文献类型：
--
作者：
Zhang, Shu-zhen;Wang, Qin-qin;Zhou, Jia-wei
背景大脑先天免疫对于维持正常的大脑功能至关重要。免疫平衡失衡在包括帕金森病(PD)在内的神经系统疾病的发病机制中起着关键作用。然而，脑天然免疫调节的分子和细胞机制及其在帕金森病发病机制中的意义仍很不清楚。方法采用Cre诱导的白喉毒素受体(IDTR)和白喉毒素介导的细胞消融方法，观察神经胶质抗原2(NG2)神经胶质细胞对脑天然免疫功能的影响。采用RNA测序技术，对NG2胶质细胞和脂多糖(LPS)刺激后小鼠脑内差异表达基因进行分析。用神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)处理小鼠，观察NG2胶质细胞存在或不存在时的神经炎性反应。免疫组织化学方法检测多巴胺能神经元存活情况或神经胶质细胞活化情况。采用NG2胶质细胞与小胶质细胞共培养的方法，检测NG2胶质细胞对小胶质细胞活化的影响。结果NG2胶质细胞通过转化生长因子-β2(TGF-β2)-转化生长因子-β2型受体(TGFBR2)-CX3C趋化因子受体1(CX3CR1)信号转导，抑制小胶质细胞的激活，维持脑内免疫稳态。我们证明，NG2胶质细胞被切除的小鼠在暴露于内毒素脂多糖后，表现出小胶质细胞特异性特征基因表达的显著下调和大脑中显著的炎症反应。功能得失研究表明，小胶质细胞中NG2胶质细胞来源的转化生长因子-β2及其受体TGFBR2是CX3CR1调节免疫反应的关键调节因子。此外，在MPTP诱导的小鼠帕金森病模型中，NG2胶质细胞的缺乏导致了神经炎症和黑质多巴胺能神经元的丢失。结论NG2神经胶质细胞在神经炎症的调节中起重要作用，为神经疾病新疗法的开发提供了有力的理论依据。
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-beta 2 (TGF-beta 2)-TGF-beta 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-beta 2 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.