title: Suppression of neuroinflammation by astrocytic dopamine D2 receptors via αB-crystallin.
abstract: 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 αB-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 neurotoxicity. 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.
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shao
authors.forename: Shu-zhen
authors.initials: SZ
authors.lastname: Zhang
authors.forename: Mi
authors.initials: M
authors.lastname: Tang
authors.forename: Xin-hua
authors.initials: XH
authors.lastname: Zhang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhou
authors.forename: Yan-qing
authors.initials: YQ
authors.lastname: Yin
authors.forename: Qin-bo
authors.initials: QB
authors.lastname: Zhou
authors.forename: Yuan-yuan
authors.initials: YY
authors.lastname: Huang
authors.forename: Ying-jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Eric
authors.initials: E
authors.lastname: Wawrousek
authors.forename: Teng
authors.initials: T
authors.lastname: Chen
authors.forename: Sheng-bin
authors.initials: SB
authors.lastname: Li
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.forename: Jiang-ning
authors.initials: JN
authors.lastname: Zhou
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
authors.forename: Jia-wei
authors.initials: JW
authors.lastname: Zhou
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000276:immunology; D018696:Neuroprotective Agents / Q000378:metabolism; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000378:metabolism*
chemical_list: C525420:Cryab protein, mouse; D018696:Neuroprotective Agents; D017448:Receptors, Dopamine D2; D038203:alpha-Crystallin B Chain; D019257:Quinpirole; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine