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Chronic neuroinflammation is a common feature of aging brain and some neurodegenerative disorders, including Parkinsons disease (PD).However, the molecular mechanism underlying the regulation of innate immunity in the central nervous system remains elusive.In the present study, we show that astrocytic dopamine D2 receptor (Drd2) modulates innate immunity through □ Bcrystallin (Cryab) that is known to suppress neuroinflammation.We demonstrate that knockout mice lacking Drd2, showed remarkable inflammatory response in multiple CNS regions and increased vulnerability of nigral dopaminergic neurons to neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity.Astrocytes null for Drd2, but not Drd1 and Drd3, became hyper-responsive to immune stimuli with dramatic reduction in the level of Cryab.Ablation of Drd2 preferentially 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.Interestingly, we found that aberrant expression of Cryab in reactive astrocytes in the ventral mesencephalon of PD patients.Furthermore, treatment of wildtype mice with a selective Drd2 agonist increased resistance of the nigral dopaminergic neurons to MPTP via partial suppression of inflammation.Our study suggests that astrocytic Drd2 activation normally suppresses neuroinflammation via a Cryab-dependent manner and provides new strategy for targeting glia-mediated pathogenesis in PD.