实验性自身免疫性脑脊髓炎（EAE）中氧化应激p38丝裂原活化蛋白激酶-血清/糖皮质激素调节激酶1信号轴的机制
Mechanism of oxidative stress p38MAPK-SGK1 signaling axis in experimental autoimmune encephalomyelitis (EAE).
作者信息
Wang Liang, Li Bin, Quan Mo-Yuan, Li Lin, Chen Yuan, Tan Guo-Jun, Zhang Jing, Liu Xiao-Peng, Guo Li
机构信息
Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China.
Key Laboratory of Hebei Neurology, Shijiazhuang, Hebei 050000, China.
出版信息
Oncotarget. 2017 Jun 27;8(26):42808-42816. doi: 10.18632/oncotarget.17057.
BACKGROUND
Multiple sclerosis (MS), a complex disease associated with multifocal demyelination of the central nervous system and poorly understood etiology. It has been previously indicated that many factors, including oxidative stress and p38MAPK-SGK1 pathway, contribute to the pathogenesis of MS.
METHODS
This study, using an experimental autoimmune encephalomyelitis (EAE) model system, was aimed at investigating the molecular mechanisms determining interaction p38MAPK-SGK1 pathway and oxidative stress in MS pathogenesis. C57BL/6 mice was immunized with MOG35-55 peptide for EAE induction, which was followed by determination of the effect of treatment with classic p38 inhibitor SB203580 and antioxidant tempol on the development and progression of EAE.
RESULTS
Our experiments showed a dynamic change of immune inflammation, oxidative stress and p38MAPK-SGK1 pathway involvement in EAE demonstrating that p38MAPK-SGK1 pathway and oxidative stress contribute to the demyelination in central nerve system caused by Th17 inflammatory responses in a synergistic way. The administration of SB203580 and Tempol both markedly suppressed the progression of EAE. Furthermore, tempol showed a strong inhibiting effect to the p38MAPK-SGK1 pathway similar to SB203580 suggesting that oxidative stress exacerbates EAE via the activation of p38MAPK-SGK1 pathway.
CONCLUSION
Cumulatively, our results show that oxidative stress p38MAPK-SGK1 signaling pathway may be a central player in EAE and even in MS.
背景
多发性硬化症（MS）是一种与中枢神经系统多灶性脱髓鞘相关的复杂疾病，其病因尚不清楚。先前已有研究表明，包括氧化应激和p38丝裂原活化蛋白激酶-血清糖皮质激素调节激酶1（p38MAPK-SGK1）信号通路在内的多种因素参与了MS的发病机制。
方法
本研究采用实验性自身免疫性脑脊髓炎（EAE）模型系统，旨在探讨在MS发病机制中决定p38MAPK-SGK1信号通路与氧化应激相互作用的分子机制。用髓鞘少突胶质细胞糖蛋白35-55（MOG35-55）肽免疫C57BL/6小鼠以诱导EAE，随后测定经典p38抑制剂SB203580和抗氧化剂Tempol对EAE发生发展的影响。
结果
我们的实验显示了EAE中免疫炎症、氧化应激和p38MAPK-SGK1信号通路参与的动态变化，表明p38MAPK-SGK1信号通路和氧化应激以协同方式促成了Th17炎症反应引起的中枢神经系统脱髓鞘。给予SB203580和Tempol均显著抑制了EAE的进展。此外，Tempol对p38MAPK-SGK1信号通路显示出与SB203580相似的强烈抑制作用，提示氧化应激通过激活p38MAPK-SGK1信号通路加重EAE。
结论
总体而言，我们的结果表明氧化应激-p38MAPK-SGK1信号通路可能在EAE甚至MS中起关键作用。
Zotero 插件