biostudies-literatureLu SZMinistry of Science and Technology of ChinaKey Realm R&D Program of Guangdong ProvinceStrategic Priority Research Program of Chinese Academy of ScienceInnovative Research Team of High-Level Local Universities in ShanghaiNational Natural Science Foundation of ChinaNINDS NIH HHSShanghai Municipal Science and Technologye20210998https://www.ebi.ac.uk/biostudies/studies/S-EPMC9350686biostudies-literatureUnknown219(9)Astrocyte activation is associated with progressive inflammatory demyelination in multiple sclerosis (MS). The molecular mechanisms underlying astrocyte activation remain incompletely understood. Recent studies have suggested that classical neurotransmitter receptors are implicated in the modulation of brain innate immunity. We investigated the role of dopamine signaling in the process of astrocyte activation. Here, we show the upregulation of dopamine D2 receptor (DRD2) in reactive astrocytes in MS brain and noncanonical role of astrocytic DRD2 in MS pathogenesis. Mice deficient in astrocytic Drd2 exhibit a remarkable suppression of reactive astrocytes and amelioration of experimental autoimmune encephalomyelitis (EAE). Mechanistically, DRD2 regulates the expression of 6-pyruvoyl-tetrahydThe Journal of experimental medicineInhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis.PMC9350686P30 NS057098U1801681R01 NS0390552018SHZDZX052018B0303370012020YFC2002800XDB32020100Xiao YCGuo YSYin YQLiang XMZhou JWLiang PZYin SLiu YFLu SZZhang XLWu YWang HYfalseInhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis.Astrocyte activation is associated with progressive inflammatory demyelination in multiple sclerosis (MS). The molecular mechanisms underlying astrocyte activation remain incompletely understood. Recent studies have suggested that classical neurotransmitter receptors are implicated in the modulation of brain innate immunity. We investigated the role of dopamine signaling in the process of astrocyte activation. Here, we show the upregulation of dopamine D2 receptor (DRD2) in reactive astrocytes in MS brain and noncanonical role of astrocytic DRD2 in MS pathogenesis. Mice deficient in astrocytic Drd2 exhibit a remarkable suppression of reactive astrocytes and amelioration of experimental autoimmune encephalomyelitis (EAE). Mechanistically, DRD2 regulates the expression of 6-pyruvoyl-tetrahyd2022-01-01T00:00:00Z2022 Sep2025-04-05T12:56:45.53Z2025-04-05T12:56:45.53ZS-EPMC93506863587759510.1084/jem.20210998