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.

• Authors: Hua Fan, Damiao Li, Xinlei Guan, Yanhui Yang, Junqiang Yan, Jian Shi, Ranran Ma, Qing Shu
• Journal: Drug design, development and therapy (Drug Des Devel Ther) Vol. 14 Pg. 1377-1389 ( 2020) ISSN: 1177-8881 [Electronic] New Zealand
• PMID: 32308370 (Publication Type: Journal Article)
• Copyright: © 2020 Fan et al.

Chemical References

• NF-kappa B
• Cuprizone
• Cybb protein, mouse
• NADPH Oxidase 2
• Methionine Sulfoxide Reductases
• methionine sulfoxide reductase
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Cuprizone
• Demyelinating Diseases (chemically induced, metabolism, prevention & control)
• Disease Models, Animal
• Inflammation (metabolism)
• Methionine Sulfoxide Reductases (deficiency, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microglia (metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• NADPH Oxidase 2 (metabolism)
• NF-kappa B (metabolism)
• Oxidative Stress
• Signal Transduction