Suppression of neuroinflammation by astrocytic dopamine D2 receptors via αB-crystallin

摘要

这项研究识别出星形细胞中的多巴胺D2受体rn(DRD2)是控制中枢神经系统(CNS)中的先天rn免疫的一个重要成分.小型热休克蛋白"B-晶rn体蛋白"(它有消炎和神经保护活性)被发现是rn这一效应的关键.在没有Drd2基因的小鼠中,rnCNS的几个区域显示出炎症迹象,同时对神经rn毒素的脆弱性也增加了.慢性炎症是衰老的大rn脑和一些神经退化疾病的一个特征,而这项研rn究表明,由CNS星形细胞介导的先天免疫反应rn有可能是衰老和疾病中一个药物作用目标.%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 aB-crystallin (CRYAB), which is known to suppress neuroinflammation. 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 neurotoxi-city. 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 wild-type 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.