Novel recombinant protein flagellin A N/C attenuates experimental autoimmune encephalomyelitis by suppressing the ROS/NF-κB/NLRP3 signaling pathway.
Novel recombinant protein flagellin A N/C attenuates experimental autoimmune encephalomyelitis by suppressing the ROS/NF-κB/NLRP3 signaling pathway.
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DOI：
10.3389/fphar.2022.956402
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发表时间：
2022
影响因子：
5.6
通讯作者：
Xu, Ying
中科院分区：
文献类型：
--
作者：
Li, Li;Deng, Shihua;Liu, Mingquan;Yang, Min;Li, Jin;Liu, Teng;Zhang, Ting;Zhao, Yangyang;He, Miao;Wu, Dongming;Xu, Ying
关键词：
多发性硬化症（MS）是一种慢性炎症性自身免疫性疾病，其特征是脱髓鞘和神经变性，传统治疗对其缓解有限。小胶质细胞/巨噬细胞的调节在MS的发病机制中起着关键作用。氧自由基的积累可引起轴突和神经细胞的损伤，并进一步促进MS的发展。我们基于嗜肺军团菌的鞭毛蛋白创建了一种新的重组蛋白，命名为C-和N-末端连接的鞭毛蛋白A（FLaAN/C），这是我们团队的自主知识产权。我们先前表明，FLaAN/C可能通过抑制炎症反应和氧化应激来减轻辐射诱导的损伤。然而，FLaAN/C是否能预防MS仍然未知。本研究观察了FLaAN/C对由少突胶质细胞糖蛋白肽35-55（MOG 35 -55）诱导的实验性自身免疫性脑脊髓炎（EAE）小鼠的抗炎作用。在出现临床症状后，腹腔注射FLaAN/C，然后每天记录临床行为评分和体重变化。模型小鼠脊髓腰段增大，伴有炎性细胞浸润和脱髓鞘，FLaAN/C可逆转上述改变。FLaAN/C还诱导小胶质细胞/巨噬细胞产生较少的促炎细胞因子（CD 86、iNOS和TNF-α）和较多的抗炎细胞因子（CD 206、IL-10和精氨酸酶-1）。这些发现表明FLaAN/C促进小胶质细胞/巨噬细胞从炎性M1极化为抗炎M2表型。此外，FLaAN/C抑制炎性细胞因子TNF-α、IL-8、IL-6、IL-17和IFN-γ的释放。这些结果表明，FLaAN/C的抗炎作用与抑制活性氧的产生有关。FLaAN/C下调磷酸化NF-κB-p65的表达，并阻止下游NLRP 3炎性小体介导的细胞凋亡。总的来说，这些结果表明，FLaAN/C通过抑制ROS/NF-κB/NLRP 3信号通路来防止细胞凋亡，并促进小胶质细胞/巨噬细胞M1/M2极化，从而显著减轻EAE小鼠模型中的炎症。我们的研究结果表明，FLaAN/C可能是MS治疗的一个有前途的候选者。
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease characterized by demyelination and neurodegeneration, for which traditional treatment offers limited relief. Microglial/macrophage modulation plays a critical role in the pathogenesis of MS. Oxygen free radical accumulation can induce axonal and nerve cell damage, and further promote MS development. We created a new recombinant protein based on flagellin from Legionella pneumophila named flagellin A with linked C- and N-terminal ends (FLaAN/C), which is an independent intellectual property of our team. We previously showed that FLaAN/C might mitigate radiation-induced damage by inhibiting inflammatory responses and oxidative stress. However, whether FLaAN/C protects against MS remains unknown. Here, we investigated the anti-inflammatory effects of FLaAN/C on mice with experimental autoimmune encephalomyelitis (EAE) induced by oligodendrocyte glycoprotein peptide 35–55 (MOG35-55). The mice were injected intraperitoneally with FLaAN/C after the onset of clinical symptoms, then clinical behavior scores and changes in body weight were recorded daily. The spinal lumbar spine in model mice was enlarged and accompanied by inflammatory cell infiltration and demyelination that were reversed by FLaAN/C. FLaAN/C also induced microglia/macrophages to generate less pro-inflammatory (CD86, iNOS, and TNF-α), and more anti-inflammatory (CD206, IL-10, and Arginase-1) cytokines. These findings suggesting that FLaAN/C promoted microglial/macrophages polarization from the inflammatory M1 to the anti-inflammatory M2 phenotype. Moreover, FLaAN/C inhibited release of the inflammatory cytokines, TNF-α, IL-8, IL-6, IL-17, and IFN-γ. These results indicated that the anti-inflammatory effect of FLaAN/C was associated with the inhibited generation of reactive oxygen species. FLaAN/C downregulated the expression of phosphorylated NF-κB-p65 and prevented downstream NLRP3 inflammasome-mediated pyroptosis. Collectively, these results indicated that FLaAN/C prevents pyroptosis by inhibiting the ROS/NF-κB/NLRP3 signaling pathway, and promotes the microglial/macrophage M1/M2 polarization that significantly alleviated inflammation in mouse models of EAE. Our findings suggested that FLaAN/C could be a promising candidate for MS therapy.
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影响因子：
12.4
作者：
Chen, Xuzhuo;Li, Chang;Cao, Xiankun;Jia, Xinlin;Chen, Xinwei;Wang, Zhenqiang;Xu, Weifeng;Dai, Fengrong;Zhang, Shanyong
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14.5
作者：
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影响因子：
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作者：
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通讯作者：
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