Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) Enhances Activation of STAT3/NLRC4 Inflammasome Signaling Axis through PKCδ in Astrocytes: Implications for Parkinson's Disease
| العنوان: | Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) Enhances Activation of STAT3/NLRC4 Inflammasome Signaling Axis through PKCδ in Astrocytes: Implications for Parkinson's Disease |
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| المؤلفون: | Anumantha G. Kanthasamy, Huajun Jin, Vellareddy Anantharam, Crystal Gomez Estrada, Chelva Janarthanam, Prashant Tarale, Gary Zenitsky, Richard D. Gordon, Manikandan Samidurai, Arthi Kanthasamy |
| المصدر: | Cells Cells, Vol 9, Iss 1831, p 1831 (2020) Volume 9 Issue 8 |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | STAT3 Transcription Factor, Cell Survival, Inflammasomes, Apoptosis, medicine.disease_cause, Article, Proinflammatory cytokine, STAT3, Mice, astrocyte, Downregulation and upregulation, TWEAK, mitochondrial dysfunction, medicine, Animals, Humans, lcsh:QH301-705.5, Cells, Cultured, NLRC4, PKCδ, biology, Chemistry, Dopaminergic Neurons, Calcium-Binding Proteins, Inflammasome, Cytokine TWEAK, Parkinson Disease, General Medicine, nervous system diseases, Cell biology, Mitochondria, CARD Signaling Adaptor Proteins, Disease Models, Animal, Oxidative Stress, Protein Kinase C-delta, lcsh:Biology (General), TWEAK Receptor, Astrocytes, STAT protein, biology.protein, Parkinson’s disease, Tumor necrosis factor alpha, Signal transduction, Inflammation Mediators, Reactive Oxygen Species, Oxidative stress, medicine.drug, Signal Transduction |
| الوصف: | Astrocytic dysfunction has been implicated in Parkinson&rsquo 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 (PKC&delta ) and signal transducer and activator of transcription 3 (STAT3) activation, accompanied by NLRC4 inflammasome activation and upregulation and release of proinflammatory cytokines, including IL-1&beta TNF-&alpha and IL-18. Mechanistically, TWEAK-induced PKC&delta activation enhances the STAT3/NLRC4 signaling pathway and other proinflammatory mediators through a mitochondrial oxidative stress-dependent mechanism. We further show that PKC&delta 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. |
| وصف الملف: | application/pdf |
| تدمد: | 2073-4409 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8620ceded1cb2c3687479334319d4d2bTest https://pubmed.ncbi.nlm.nih.gov/32759670Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8620ceded1cb2c3687479334319d4d2b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20734409 |
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