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MsrA Suppresses Inflammatory Activation of Microglia and Oxidative Stress to Prevent Demyelination via Inhibition of the NOX2-MAPKs/NF-κB Signaling Pathway

INTRODUCTION: Demyelination causes neurological deficits involving visual, motor, sensory symptoms. Deregulation of several enzymes has been identified in demyelination, which holds potential for the development of treatment strategies for demyelination. However, the specific effect of methionine su...

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Autores principales: Fan, Hua, Li, Damiao, Guan, Xinlei, Yang, Yanhui, Yan, Junqiang, Shi, Jian, Ma, Ranran, Shu, Qing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147623/
https://www.ncbi.nlm.nih.gov/pubmed/32308370
http://dx.doi.org/10.2147/DDDT.S223218
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author Fan, Hua
Li, Damiao
Guan, Xinlei
Yang, Yanhui
Yan, Junqiang
Shi, Jian
Ma, Ranran
Shu, Qing
author_facet Fan, Hua
Li, Damiao
Guan, Xinlei
Yang, Yanhui
Yan, Junqiang
Shi, Jian
Ma, Ranran
Shu, Qing
author_sort Fan, Hua
collection PubMed
description INTRODUCTION: Demyelination causes neurological deficits involving visual, motor, sensory symptoms. Deregulation of several enzymes has been identified in demyelination, which holds potential for the development of treatment strategies for demyelination. However, the specific effect of methionine sulfoxide reductase A (MsrA) on demyelination remains unclear. Hence, this study aims to explore the effect of MsrA on oxidative stress and inflammatory response of microglia in demyelination. METHODS: Initially, we established a mouse model with demyelination induced by cuprizone and a cell model provoked by lipopolysaccharide (LPS). The expression of MsrA in wild-type (WT) and MsrA-knockout (MsrA(-/-)) mice were determined by RT-qPCR and Western blot analysis. In order to further explore the function of MsrA on inflammatory response, and oxidative stress in demyelination, we detected the expression of microglia marker Iba1, inflammatory factors TNF-α and IL-1β and intracellular reactive oxygen species (ROS), superoxide dismutase (SOD) activity, as well as expression of the NOX2-MAPKs/NF-κB signaling pathway-related genes in MsrA(-/-) mice and LPS-induced microglia following different treatments. RESULTS: MsrA expression was downregulated in MsrA(-/-) mice. MsrA silencing was shown to produce severely injured motor coordination, increased expressions of Iba1, TNF-α, IL-1β, ROS and NOX2, and extent of ERK, p38, IκBα, and p65 phosphorylation, but reduced SOD activity. Conjointly, our study suggests that Tat-MsrA fusion protein can prevent the cellular inflammatory response and subsequent demyelination through negative regulation of the NOX2-MAPKs/NF-κB signaling pathway. CONCLUSION: Our data provide a profound insight on the role of endogenous antioxidative defense systems such as MsrA in controlling microglial function.
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spelling pubmed-71476232020-04-17 MsrA Suppresses Inflammatory Activation of Microglia and Oxidative Stress to Prevent Demyelination via Inhibition of the NOX2-MAPKs/NF-κB Signaling Pathway Fan, Hua Li, Damiao Guan, Xinlei Yang, Yanhui Yan, Junqiang Shi, Jian Ma, Ranran Shu, Qing Drug Des Devel Ther Original Research INTRODUCTION: Demyelination causes neurological deficits involving visual, motor, sensory symptoms. Deregulation of several enzymes has been identified in demyelination, which holds potential for the development of treatment strategies for demyelination. However, the specific effect of methionine sulfoxide reductase A (MsrA) on demyelination remains unclear. Hence, this study aims to explore the effect of MsrA on oxidative stress and inflammatory response of microglia in demyelination. METHODS: Initially, we established a mouse model with demyelination induced by cuprizone and a cell model provoked by lipopolysaccharide (LPS). The expression of MsrA in wild-type (WT) and MsrA-knockout (MsrA(-/-)) mice were determined by RT-qPCR and Western blot analysis. In order to further explore the function of MsrA on inflammatory response, and oxidative stress in demyelination, we detected the expression of microglia marker Iba1, inflammatory factors TNF-α and IL-1β and intracellular reactive oxygen species (ROS), superoxide dismutase (SOD) activity, as well as expression of the NOX2-MAPKs/NF-κB signaling pathway-related genes in MsrA(-/-) mice and LPS-induced microglia following different treatments. RESULTS: MsrA expression was downregulated in MsrA(-/-) mice. MsrA silencing was shown to produce severely injured motor coordination, increased expressions of Iba1, TNF-α, IL-1β, ROS and NOX2, and extent of ERK, p38, IκBα, and p65 phosphorylation, but reduced SOD activity. Conjointly, our study suggests that Tat-MsrA fusion protein can prevent the cellular inflammatory response and subsequent demyelination through negative regulation of the NOX2-MAPKs/NF-κB signaling pathway. CONCLUSION: Our data provide a profound insight on the role of endogenous antioxidative defense systems such as MsrA in controlling microglial function. Dove 2020-04-05 /pmc/articles/PMC7147623/ /pubmed/32308370 http://dx.doi.org/10.2147/DDDT.S223218 Text en © 2020 Fan et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Fan, Hua
Li, Damiao
Guan, Xinlei
Yang, Yanhui
Yan, Junqiang
Shi, Jian
Ma, Ranran
Shu, Qing
MsrA Suppresses Inflammatory Activation of Microglia and Oxidative Stress to Prevent Demyelination via Inhibition of the NOX2-MAPKs/NF-κB Signaling Pathway
title MsrA Suppresses Inflammatory Activation of Microglia and Oxidative Stress to Prevent Demyelination via Inhibition of the NOX2-MAPKs/NF-κB Signaling Pathway
title_full MsrA Suppresses Inflammatory Activation of Microglia and Oxidative Stress to Prevent Demyelination via Inhibition of the NOX2-MAPKs/NF-κB Signaling Pathway
title_fullStr MsrA Suppresses Inflammatory Activation of Microglia and Oxidative Stress to Prevent Demyelination via Inhibition of the NOX2-MAPKs/NF-κB Signaling Pathway
title_full_unstemmed MsrA Suppresses Inflammatory Activation of Microglia and Oxidative Stress to Prevent Demyelination via Inhibition of the NOX2-MAPKs/NF-κB Signaling Pathway
title_short MsrA Suppresses Inflammatory Activation of Microglia and Oxidative Stress to Prevent Demyelination via Inhibition of the NOX2-MAPKs/NF-κB Signaling Pathway
title_sort msra suppresses inflammatory activation of microglia and oxidative stress to prevent demyelination via inhibition of the nox2-mapks/nf-κb signaling pathway
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147623/
https://www.ncbi.nlm.nih.gov/pubmed/32308370
http://dx.doi.org/10.2147/DDDT.S223218
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