MsrA Suppresses Inflammatory Activation of Microglia and Oxidative Stress to Prevent Demyelination via Inhibition of the NOX2-MAPKs/NF-κB Signaling Pathway
MsrA Suppresses Inflammatory Activation of Microglia and Oxidative Stress to Prevent Demyelination via Inhibition of the NOX2-MAPKs/NF-κB Signaling Pathway
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MsrA 通过抑制 NOX2-MAPKs/NF-kappa B 信号通路来抑制小胶质细胞的炎症激活和氧化应激，从而防止脱髓鞘
DOI：
10.2147/dddt.s223218
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发表时间：
2020-01-01
影响因子：
4.8
通讯作者：
Shu, Qing
中科院分区：
文献类型：
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作者：
Fan, Hua;Li, Damiao;Shu, Qing
脱髓鞘导致神经功能缺损，包括视觉、运动和感觉症状。在脱髓鞘中已经确定了几种酶的解除管制，这对于脱髓鞘治疗策略的发展具有潜力。然而，蛋氨酸亚砜还原酶A （MsrA）对脱髓鞘的具体作用尚不清楚。因此，本研究旨在探讨MsrA对脱髓鞘小胶质细胞氧化应激和炎症反应的影响。方法：首先建立铜酮诱导小鼠脱髓鞘模型和脂多糖（LPS）诱导的细胞模型。采用RT-qPCR和Western blot检测野生型（WT）和敲除MsrA（-/-）小鼠中MsrA的表达。为了进一步探讨MsrA对炎症反应和脱髓鞘氧化应激的作用，我们检测了不同处理后MsrA（-/-）小鼠和lps诱导的小胶质细胞中小胶质细胞标志物Iba1、炎症因子tnf - α和IL-1 β的表达、细胞内活性氧（ROS）、超氧化物歧化酶（SOD）活性以及NOX2-MAPKs/NF-kappa B信号通路相关基因的表达。结果：MsrA（-/-）小鼠的MsrA表达下调。结果显示，MsrA沉默导致运动协调能力严重受损，Iba1、tnf - α、IL-1 β、ROS和NOX2表达增加，ERK、p38、I κ B α和p65磷酸化程度增加，SOD活性降低。同时，我们的研究表明，tata - msra融合蛋白可以通过负调控NOX2-MAPKs/NF-kappa B信号通路来阻止细胞炎症反应和随后的脱髓鞘。结论：我们的数据为内源性抗氧化防御系统如MsrA在控制小胶质细胞功能中的作用提供了深刻的见解。
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-alpha and IL-1 beta and intracellular reactive oxygen species (ROS), superoxide dismutase (SOD) activity, as well as expression of the NOX2-MAPKs/NF-kappa B 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-alpha, IL-1 beta, ROS and NOX2, and extent of ERK, p38, I kappa B alpha, 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-kappa B signaling pathway.Conclusion: Our data provide a profound insight on the role of endogenous antioxidative defense systems such as MsrA in controlling microglial function.