星形胶质细胞在多种神经退行性疾病中对慢性神经炎症的贡献，包括帕金森病（PD），这是最常见的运动障碍。然而，星形胶质细胞在神经炎症中的精确作用尚未完全了解。在这里，我们展示了G蛋白信号调节蛋白5（RGS5）通过增强星形胶质细胞肿瘤坏死因子受体（TNFR）信号通路来促进神经退行性过程。我们发现，在星形胶质细胞中选择性消除Rgs5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的过度表达则具有相反的效果。在机械上，RGS5蛋白通过与TNFR2受体结合，将星形胶质细胞从神经保护性转变为促炎性状态。RGS5还通过与TNFR1受体相互作用，增强了TNFR信号介导的促炎反应。此外，通过RGS5 aa 1-108或小分子化合物feshurin和butein中断RGS5 / TNFR相互作用，可以抑制星形胶质细胞的细胞因子产生。我们发现，星形胶质细胞RGS5的转录受由转录因子早期B细胞因子1控制，而RGS5调控的TNF信号则相互影响早期B细胞因子1的表达。因此，我们的研究表明，除了其在G蛋白偶联受体信号转导中的传统作用外，星形胶质细胞RGS5还是TNF信号通路的关键调节因子，从而激活了星形胶质细胞并促进慢性神经炎症的发生。阻断星形胶质细胞RGS5 / TNFR相互作用可能是治疗神经炎症相关神经退行性疾病的潜在策略。 © 2023. BioMed Central Ltd., part of Springer Nature.

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.© 2023. BioMed Central Ltd., part of Springer Nature.