Department of Neurology, Division of Multiple Sclerosis and Neuroimmunology, Northwestern University Feinberg School of Medicine, Chicago, United States.
Weill Institute for Neuroscience, Department of Neurology, University of California, San Francisco, San Francisco, United States.
Elife. 2021 Mar 23;10:e65469. doi: 10.7554/eLife.65469.
The inflammatory environment of demyelinated lesions in multiple sclerosis (MS) patients contributes to remyelination failure. Inflammation activates a cytoprotective pathway, the integrated stress response (ISR), but it remains unclear whether enhancing the ISR can improve remyelination in an inflammatory environment. To examine this possibility, the remyelination stage of experimental autoimmune encephalomyelitis (EAE), as well as a mouse model that incorporates cuprizone-induced demyelination along with CNS delivery of the proinflammatory cytokine IFN-γ were used here. We demonstrate that either genetic or pharmacological ISR enhancement significantly increased the number of remyelinating oligodendrocytes and remyelinated axons in the inflammatory lesions. Moreover, the combined treatment of the ISR modulator Sephin1 with the oligodendrocyte differentiation enhancing reagent bazedoxifene increased myelin thickness of remyelinated axons to pre-lesion levels. Taken together, our findings indicate that prolonging the ISR protects remyelinating oligodendrocytes and promotes remyelination in the presence of inflammation, suggesting that ISR enhancement may provide reparative benefit to MS patients.
多发性硬化症（MS）患者脱髓鞘病变中的炎症环境导致髓鞘再生失败。炎症激活了一种细胞保护途径，即整合应激反应（ISR），但尚不清楚增强 ISR 是否能改善炎症环境中的髓鞘再生。为了检验这种可能性，本研究使用实验性自身免疫性脑脊髓炎（EAE）的髓鞘再生阶段，以及一种将杯状肽诱导的脱髓鞘与中枢神经系统内递送促炎细胞因子 IFN-γ结合的小鼠模型。我们证明，无论是遗传还是药理学增强 ISR，都能显著增加炎症病灶中髓鞘再生少突胶质细胞和髓鞘再生轴突的数量。此外，ISR 调节剂 Sephin1 与少突胶质细胞分化增强剂巴泽多昔芬联合治疗可使髓鞘再生轴突的厚度恢复到病变前水平。总之，我们的研究结果表明，延长 ISR 可保护髓鞘再生少突胶质细胞并促进炎症环境中的髓鞘再生，提示增强 ISR 可能为 MS 患者提供修复益处。
