Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis [spinal cord]

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 non-canonical role of astrocytic DRD2 in MS pathogenesis. Mice deficient in astrocytic Drd2 exhibit a remarkable suppression of reactive astrocytes and inflammation which are highly correlated with the amelioration of experimental autoimmune encephalomyelitis (EAE). Mechanistically, DRD2 regulates the expression of 6-pyruvoyl-tetrahydropterin synthase which modulates NF-kappaB activity through protein kinase C-delta. Pharmacological blockade of astrocytic DRD2 with a DRD2 antagonist dehydrocorybulbine remarkably inhibits the inflammatory response in mice lacking Drd2 in neurons. Together, our findings reveal previously uncharted roles for a DRD2 in astrocyte activation during EAE-associated CNS inflammation. Its therapeutic inhibition may provide a potent lever to alleviate autoimmune diseases.星形胶质细胞活化与多发性硬化（multiple sclerosis, MS）中的进行性炎性脱髓鞘病变密切相关。目前，星形胶质细胞活化的分子机制尚未完全阐明。已有研究提示，经典神经递质受体参与调控大脑固有免疫应答。本研究聚焦多巴胺信号通路在星形胶质细胞活化过程中的作用。研究结果显示，多发性硬化患者脑组织内的反应性星形胶质细胞中，多巴胺D2受体（dopamine D2 receptor, DRD2）表达上调，且星形胶质细胞DRD2在多发性硬化发病机制中发挥此前未被报道的非经典调控功能。星形胶质细胞特异性敲除Drd2的小鼠，其反应性星形胶质细胞活化与炎症反应均受到显著抑制，且该表型与实验性自身免疫性脑脊髓炎（experimental autoimmune encephalomyelitis, EAE）的病情改善高度相关。机制研究表明，DRD2可调控6-丙酮酰四氢蝶呤合酶的表达，该酶通过蛋白激酶Cδ（protein kinase C-delta）调控核因子κB（NF-κB）的活性。采用DRD2拮抗剂脱氢紫堇碱对星形胶质细胞DRD2进行药理学阻断，可显著抑制神经元特异性敲除Drd2的小鼠体内的炎症反应。综上，本研究揭示了DRD2在实验性自身免疫性脑脊髓炎相关中枢神经系统（central nervous system, CNS）炎症过程中星形胶质细胞活化环节的全新调控作用，靶向抑制DRD2或可为自身免疫性疾病的治疗提供有效干预手段。