Astrocytic dysfunction has been implicated in Parkinson’s disease (PD) pathogenesis. While the Tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/Fn14 signaling axis is known to play a role in PD-like neuropathology, the molecular mechanisms that govern this process remain poorly understood. Herein, we show that TWEAK levels are elevated in PD serum compared to controls. Moreover, using both U373 human astrocyte cells and primary mouse astrocytes, we demonstrate that TWEAK induces mitochondrial oxidative stress as well as protein kinase C delta (PKCδ) and signal transducer and activator of transcription 3 (STAT3) activation, accompanied by NLRC4 inflammasome activation and upregulation and release of proinflammatory cytokines, including IL-1β, TNF-α, and IL-18. Mechanistically, TWEAK-induced PKCδ activation enhances the STAT3/NLRC4 signaling pathway and other proinflammatory mediators through a mitochondrial oxidative stress-dependent mechanism. We further show that PKCδ knockdown and mito-apocynin, a mitochondrial antioxidant, suppress TWEAK-induced proinflammatory NLRC4/STAT3 signaling and cellular oxidative stress response. Notably, we validated our in vitro findings in an MPTP mouse model of PD and in mice receiving intrastriatal administration of TWEAK. These results indicate that TWEAK is a key regulator of astroglial reactivity and illustrate a novel mechanism by which mitochondrial oxidative stress may influence dopaminergic neuronal survival in PD.

中文翻译：

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肿瘤坏死因子样细胞凋亡弱诱导物（TWEAK）通过星形胶质细胞中的PKCδ增强STAT3 / NLRC4炎性小体信号轴的激活：对帕金森氏病的意义。

星形细胞功能障碍与帕金森氏病（PD）发病机理有关。虽然已知肿瘤坏死因子样凋亡的弱诱导物（TWEAK）/ Fn14信号轴在PD样神经病理学中起作用，但控制这一过程的分子机制仍知之甚少。在本文中，我们显示与对照相比，PD血清中的TWEAK水平升高。此外，我们同时使用U373人星形胶质细胞和原代小鼠星形胶质细胞，证明TWEAK诱导线粒体氧化应激以及蛋白激酶Cδ（PKCδ）和信号转导和转录激活因子3（STAT3）激活，并伴有NLRC4炎性体激活和促炎细胞因子（包括IL-1β，TNF-α和IL-18）的上调和释放。机械上，TWEAK诱导的PKCδ激活通过线粒体氧化应激依赖性机制增强STAT3 / NLRC4信号通路和其他促炎介质。我们进一步表明，PKCδ敲低和线粒体抗氧化剂线粒-apocynin，抑制TWEAK诱导的促炎性NLRC4 / STAT3信号传导和细胞氧化应激反应。值得注意的是，我们在PD的MPTP小鼠模型和接受纹状体内施用TWEAK的小鼠中验证了我们的体外发现。这些结果表明，TWEAK是星形胶质细胞反应性的关键调节剂，并说明线粒体氧化应激可能影响PD中多巴胺能神经元存活的新机制。线粒体抗氧化剂，抑制TWEAK诱导的促炎性NLRC4 / STAT3信号转导和细胞氧化应激反应。值得注意的是，我们在PD的MPTP小鼠模型和接受纹状体内施用TWEAK的小鼠中验证了我们的体外发现。这些结果表明，TWEAK是星形胶质细胞反应性的关键调节剂，并说明线粒体氧化应激可能影响PD中多巴胺能神经元存活的新机制。线粒体抗氧化剂，抑制TWEAK诱导的促炎性NLRC4 / STAT3信号转导和细胞氧化应激反应。值得注意的是，我们在PD的MPTP小鼠模型和接受纹状体内施用TWEAK的小鼠中验证了我们的体外发现。这些结果表明，TWEAK是星形胶质细胞反应性的关键调节剂，并说明线粒体氧化应激可能影响PD中多巴胺能神经元存活的新机制。