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

Abstract

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.

Keywords:

• demyelination
• MsrA
• NOX2-MAPKs/NF-κB signaling pathway
• microglia
• oxidative stress
• inflammatory activation

Acknowledgment

We acknowledge and appreciate our colleagues for their valuable efforts and comments on this paper.

Author Contributions

Hua Fan, Damiao Li and Xinlei Guan designed the study. Yanhui Yang, Junqiang Yan and Jian Shi collected the data, carried out data analyses and produced the initial draft of the manuscript. Ranran Ma and Qing Shu contributed to drafting the manuscript. All authors contributed towards data analysis, drafting and critically revising the paper, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.