Suppression of neuroinflammation by astrocytic dopamine D2 receptors via αB-crystallin
Suppression of neuroinflammation by astrocytic dopamine D2 receptors via αB-crystallin
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DOI：
10.1038/nature11748
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发表时间：
2013-02-07
期刊：
影响因子：
64.8
通讯作者：
Zhou, Jia-wei
中科院分区：
文献类型：
--
作者：
Shao, Wei;Zhang, Shu-zhen;Zhou, Jia-wei
慢性神经炎症是大脑老化和一些神经退行性疾病的共同特征。然而，中枢神经系统中先天免疫调节的分子和细胞机制仍然难以捉摸。在这里，我们表明星形胶质细胞多巴胺D2受体（DRD 2）通过α B-晶体蛋白（α B-晶体蛋白）调节先天免疫，这是已知的抑制神经炎症（1，2）。我们证明，缺乏Drd 2的基因敲除小鼠在多个中枢神经系统区域显示出显著的炎症反应，并增加了黑质多巴胺能神经元对神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的神经毒性的脆弱性（3）。星形胶质细胞无效的Drd 2成为高度反应性的免疫刺激与显着减少的水平，ESTAB。在星形胶质细胞中优先消融Drd 2可强烈激活黑质中的星形胶质细胞。获得或丧失功能的研究表明，DRD 2介导的调节星形胶质细胞中的先天免疫应答，ESTAB是至关重要的。此外，用选择性DRD 2激动剂喹吡罗治疗野生型小鼠通过部分抑制炎症增加了黑质多巴胺能神经元对MPTP的抗性。我们的研究表明，星形胶质细胞DRD 2激活通常通过一种依赖于GABA的机制抑制中枢神经系统的神经炎症，并为在衰老和疾病期间靶向中枢神经系统中星形胶质细胞介导的先天免疫反应提供了一种新的策略。
Chronic neuroinflammation is a common feature of the ageing brain and some neurodegenerative disorders. However, the molecular and cellular mechanisms underlying the regulation of innate immunity in the central nervous system remain elusive. Here we show that the astrocytic dopamine D2 receptor (DRD2) modulates innate immunity through alpha B-crystallin (CRYAB), which is known to suppress neuroinflammation(1,2). We demonstrate that knockout mice lacking Drd2 showed remarkable inflammatory response in multiple central nervous system regions and increased the vulnerability of nigral dopaminergic neurons to neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity(3). Astrocytes null for Drd2 became hyper-responsive to immune stimuli with a marked reduction in the level of CRYAB. Preferential ablation of Drd2 in astrocytes robustly activated astrocytes in the substantia nigra. Gain- or loss-of-function studies showed that CRYAB is critical for DRD2-mediated modulation of innate immune response in astrocytes. Furthermore, treatment of wildtype mice with the selective DRD2 agonist quinpirole increased resistance of the nigral dopaminergic neurons to MPTP through partial suppression of inflammation. Our study indicates that astrocytic DRD2 activation normally suppresses neuroinflammation in the central nervous system through a CRYAB-dependent mechanism, and provides a new strategy for targeting the astrocyte-mediated innate immune response in the central nervous system during ageing and disease.