Inhibition 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...

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Published inThe Journal of experimental medicine Vol. 219; no. 9
Main Authors Lu, Shen-Zhao, Wu, Yue, Guo, Yong-Shun, Liang, Pei-Zhou, Yin, Shu, Yin, Yan-Qing, Zhang, Xiu-Li, Liu, Yan-Fang, Wang, Hong-Yan, Xiao, Yi-Chuan, Liang, Xin-Miao, Zhou, Jia-Wei
Format Journal Article
LanguageEnglish
Published United States Rockefeller University Press 05.09.2022
Subjects
Animals
Astrocytes - metabolism
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental
Inflammation - pathology
Innate Immunity and Inflammation
Mice
Mice, Inbred C57BL
Multiple Sclerosis - pathology
Neuroinflammation
Receptors, Dopamine D2 - metabolism
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Summary: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-κB activity through protein kinase C-δ. 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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S.-z. Lu, Y. Wu, Y.-s. Guo, P.-z. Liang, and S. Yin contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20210998