期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 219, 期 9, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20210998
关键词
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资金
- Ministry of Science and Technology of China [2020YFC2002800]
- Natural Science Foundation of China [U1801681]
- Strategic Priority Research Program of Chinese Academy of Science [XDB32020100]
- Shanghai Municipal Science and Technology Major Project [2018SHZDZX05]
- Key Realm R&D Program of Guangdong Province [2018B030337001]
- Innovative Research Team of High-Level Local Universities in Shanghai
This study reveals a previously unknown role for dopamine D2 receptor (DRD2) in astrocyte activation during central nervous system inflammation associated with experimental autoimmune encephalomyelitis (EAE). Blocking astrocytic DRD2 can inhibit the inflammatory response.
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-tetrahydropterin synthase, which modulates NF-kappa B activity through protein kinase C-delta. Pharmacological blockade of astrocytic DRD2 with a DRD2 antagonist dehydrocorybulbine remarkably inhibits the inflammatory response in mice lacking neuronal Drd2. Together, our findings reveal previously an uncharted role for DRD2 in astrocyte activation during EAE-associated CNS inflammation. Its therapeutic inhibition may provide a potent lever to alleviate autoimmune diseases.
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