Dopamine receptor D3 signalling in astrocytes promotes neuroinflammation
Dopamine receptor D3 signalling in astrocytes promotes neuroinflammation
复制标题
DOI：
10.1186/s12974-019-1652-8
复制
发表时间：
2019-12-06
影响因子：
9.3
通讯作者：
Pacheco, Rodrigo
中科院分区：
文献类型：
--
作者：
Montoya, Andro;Elgueta, Daniela;Pacheco, Rodrigo
背景神经炎症是导致阿尔茨海默病、帕金森病和脓毒症等多种疾病的神经退行性变的致病过程。尽管小胶质细胞是神经炎症的中心参与者，但星形胶质细胞在这一过程中发挥着关键的调节作用。我们以前的结果表明，药物拮抗或遗传缺陷的多巴胺受体D3(DRD3)可以减轻两种帕金森病小鼠模型的神经炎症和神经变性。在这里，我们研究了在全身炎症的背景下，DRD3信号如何影响小胶质细胞和星形胶质细胞的激活动态。方法采用内毒素诱导大鼠神经炎性反应模型。免疫组织化学和流式细胞仪检测不同时间点DRD3基因缺失或药物拮抗对星形胶质细胞和小胶质细胞功能表型的影响。结果DRD3在星形胶质细胞中表达，而在小胶质细胞中不表达。DRD3缺乏导致星形胶质细胞无反应，并在全身炎症时减弱小胶质细胞的激活。此外，DRD3拮抗和DRD3基因缺陷在脂多糖刺激下也观察到神经胶质细胞功能表型的类似变化。机制分析表明，DRD3缺乏导致抗炎蛋白Fizz1在体外和体内胶质细胞中的表达加剧。结论DRD3信号调节星形胶质细胞和小胶质细胞获得促炎和抗炎功能的动态过程，最终有利于小胶质细胞的激活，促进神经炎症。
Background Neuroinflammation constitutes a pathogenic process leading to neurodegeneration in several disorders, including Alzheimer's disease, Parkinson's disease (PD) and sepsis. Despite microglial cells being the central players in neuroinflammation, astrocytes play a key regulatory role in this process. Our previous results indicated that pharmacologic-antagonism or genetic deficiency of dopamine receptor D3 (DRD3) attenuated neuroinflammation and neurodegeneration in two mouse models of PD. Here, we studied how DRD3-signalling affects the dynamic of activation of microglia and astrocyte in the context of systemic inflammation. Methods Neuroinflammation was induced by intraperitoneal administration of LPS. The effect of genetic DRD3-deficiency or pharmacologic DRD3-antagonism in the functional phenotype of astrocytes and microglia was determined by immunohistochemistry and flow cytometry at different time-points. Results Our results show that DRD3 was expressed in astrocytes, but not in microglial cells. DRD3 deficiency resulted in unresponsiveness of astrocytes and in attenuated microglial activation upon systemic inflammation. Furthermore, similar alterations in the functional phenotypes of glial cells were observed by DRD3 antagonism and genetic deficiency of DRD3 upon LPS challenge. Mechanistic analyses show that DRD3 deficiency resulted in exacerbated expression of the anti-inflammatory protein Fizz1 in glial cells both in vitro and in vivo. Conclusions These results suggest that DRD3 signalling regulates the dynamic of the acquisition of pro-inflammatory and anti-inflammatory features by astrocytes and microglia, finally favouring microglial activation and promoting neuroinflammation.