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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

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 understoo...

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Autores principales: Samidurai, Manikandan, Tarale, Prashant, Janarthanam, Chelva, Estrada, Crystal Gomez, Gordon, Richard, Zenitsky, Gary, Jin, Huajun, Anantharam, Vellareddy, Kanthasamy, Anumantha G., Kanthasamy, Arthi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464730/
https://www.ncbi.nlm.nih.gov/pubmed/32759670
http://dx.doi.org/10.3390/cells9081831
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author Samidurai, Manikandan
Tarale, Prashant
Janarthanam, Chelva
Estrada, Crystal Gomez
Gordon, Richard
Zenitsky, Gary
Jin, Huajun
Anantharam, Vellareddy
Kanthasamy, Anumantha G.
Kanthasamy, Arthi
author_facet Samidurai, Manikandan
Tarale, Prashant
Janarthanam, Chelva
Estrada, Crystal Gomez
Gordon, Richard
Zenitsky, Gary
Jin, Huajun
Anantharam, Vellareddy
Kanthasamy, Anumantha G.
Kanthasamy, Arthi
author_sort Samidurai, Manikandan
collection PubMed
description 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.
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spelling pubmed-74647302020-09-04 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 Samidurai, Manikandan Tarale, Prashant Janarthanam, Chelva Estrada, Crystal Gomez Gordon, Richard Zenitsky, Gary Jin, Huajun Anantharam, Vellareddy Kanthasamy, Anumantha G. Kanthasamy, Arthi Cells Article 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. MDPI 2020-08-04 /pmc/articles/PMC7464730/ /pubmed/32759670 http://dx.doi.org/10.3390/cells9081831 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Samidurai, Manikandan
Tarale, Prashant
Janarthanam, Chelva
Estrada, Crystal Gomez
Gordon, Richard
Zenitsky, Gary
Jin, Huajun
Anantharam, Vellareddy
Kanthasamy, Anumantha G.
Kanthasamy, Arthi
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464730/
https://www.ncbi.nlm.nih.gov/pubmed/32759670
http://dx.doi.org/10.3390/cells9081831
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