PDF(Pubmed)
Abstract：
Astrocytes contribute to chronic neuroinflammation in a variety of neurodegenerative diseases, including Parkinson\'s disease (PD), the most common movement disorder. However, the precise role of astrocytes in neuroinflammation remains incompletely understood. Herein, we show that regulator of G-protein signaling 5 (RGS5) promotes neurodegenerative process through augmenting astrocytic tumor necrosis factor receptor (TNFR) signaling. We found that selective ablation of Rgs5 in astrocytes caused an inhibition in the production of cytokines resulting in mitigated neuroinflammatory response and neuronal survival in animal models of PD, whereas overexpression of Rgs5 had the opposite effects. Mechanistically, RGS5 switched astrocytes from neuroprotective to pro-inflammatory property via binding to the receptor TNFR2. RGS5 also augmented TNFR signaling-mediated pro-inflammatory response by interacting with the receptor TNFR1. Moreover, interrupting RGS5/TNFR interaction by either RGS5 aa 1-108 or small molecular compounds feshurin and butein, suppressed astrocytic cytokine production. We showed that the transcription of astrocytic RGS5 was controlled by transcription factor early B cell factor 1 whose expression was reciprocally influenced by RGS5-modulated TNF signaling. Thus, our study indicates that beyond its traditional role in G-protein coupled receptor signaling, astrocytic RGS5 is a key modulator of TNF signaling circuit with resultant activation of astrocytes thereby contributing to chronic neuroinflammation. Blockade of the astrocytic RGS5/TNFR interaction is a potential therapeutic strategy for neuroinflammation-associated neurodegenerative diseases.
摘要：
星形胶质细胞有助于各种神经退行性疾病的慢性神经炎症，包括帕金森病（PD），最常见的运动障碍。然而,星形胶质细胞在神经炎症中的确切作用尚不完全清楚.在这里，我们发现G蛋白信号调节因子5(RGS5)通过增强星形细胞肿瘤坏死因子受体(TNFR)信号促进神经退行性过程.我们发现星形胶质细胞中Rgs5的选择性消融会抑制细胞因子的产生，从而减轻PD动物模型中的神经炎症反应和神经元存活，而Rgs5的过表达具有相反的作用。机械上,RGS5通过与受体TNFR2结合，将星形胶质细胞从神经保护特性转变为促炎特性。RGS5还通过与受体TNFR1相互作用来增强TNFR信号传导介导的促炎反应。此外，通过RGS5aa1-108或小分子化合物feshurin和butein中断RGS5/TNFR相互作用，抑制星形细胞细胞因子的产生。我们表明星形胶质细胞RGS5的转录受转录因子早期B细胞因子1的控制，其表达受RGS5调节的TNF信号传导的相互影响。因此，我们的研究表明，除了其在G蛋白偶联受体信号传导中的传统作用外，星形胶质细胞RGS5是TNF信号传导回路的关键调节剂，并激活星形胶质细胞，从而导致慢性神经炎症。星形胶质细胞RGS5/TNFR相互作用的阻断是神经炎症相关神经退行性疾病的潜在治疗策略。
