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Astrocyte-microglia communication influences the onset and progression of central nervous system (CNS) disorders. In this study, we determined how chronic inflammation by activated astrocytes affected and regulated CNS functions in Sandhoff disease (SD), a CNS lysosomal storage disorder. SD triggers intense CNS inflammation such as microglial activation and astrogliosis. It is caused by mutation of the HEXB gene, which reduces β-hexosaminidase (Hex) enzymatic activity in lysosomes, leading to accumulation of the substrate GM2 ganglioside in neuronal cells. Hexb -/- mice display a phenotype similar to human patients that suffer from chronic inflammation characterized by activation of astrocytes and microglia. In Hexb -/- mice, tremors and loss of muscle coordination begins at ~12 weeks. Interestingly, we found that reactive astrocytes expressed adenosine A 2A receptor in the cerebral cortices of Hexb -/- mice at the later inflammatory phase. In cultured astrocytes, expression of A 2A receptor could be induced by astrocyte defined medium, and then the activation of the A 2A receptor induced ccl2 expression. In Hexb -/- mice, inhibition of the A 2A receptor antagonized by istradefylline decreased the number of activated microglial cells and inflammatory cytokines/chemokines at 13 weeks. Thus, the astrocytic A 2A receptor is an important sensor that regulates microglial activation in the late phase of inflammation., (Copyright © 2018 Elsevier Inc. All rights reserved.)