Fingolimod Protects Against Ischemic White Matter Damage by Modulating Microglia Toward M2 Polarization via STAT3 Pathway.
Fingolimod Protects Against Ischemic White Matter Damage by Modulating Microglia Toward M2 Polarization via STAT3 Pathway.
复制标题
芬戈莫德通过 STAT3 通路调节小胶质细胞向 M2 极化，从而防止缺血性白质损伤。
DOI：
10.1161/strokeaha.117.018505
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发表时间：
2017-12
期刊：
影响因子：
8.3
通讯作者：
Tian DS
中科院分区：
文献类型：
--
作者：
Qin C;Fan WH;Liu Q;Shang K;Murugan M;Wu LJ;Wang W;Tian DS
脑白质缺血性损伤是脑血管疾病的主要神经病理特征，是导致老年血管性认知障碍的重要原因。WM缺血性损伤后脱髓鞘的发病机制常伴有小胶质细胞活化。Fingolimod （FTY720）因其免疫抑制特性被批准用于治疗多发性硬化症。在本研究中，我们评估了FTY720在脑缺血模型中的神经保护作用。建立双侧颈动脉狭窄（BCAS）致WM慢性缺血性损伤模型。评估BCAS后的认知功能、WM完整性、小胶质细胞激活和参与小胶质细胞极化的潜在通路。通过Luxol快速蓝染色、免疫荧光染色和电镜观察，胼胝体脱髓鞘和朗维耶淋巴结组织紊乱是WM完整性破坏的特征。此外，径向迷宫测试显示，bcas损伤后1个月，大鼠的工作记忆能力下降。有趣的是，FTY720可以减少认知能力下降，改善WM完整性的破坏。从机制上讲，脑灌注不足诱导小胶质细胞激活，产生相关的促炎细胞因子和引发小胶质细胞向M1表型的极化；而FTY720可减轻小胶质细胞介导的WM缺血后的神经炎症，并通过将小胶质细胞向M2极化转移来促进少突胶质细胞的发生。在体外实验中，FTY720对小胶质细胞M2极化的影响在很大程度上被STAT3选择性阻断所抑制，这表明FTY720使小胶质细胞从M1向M2极化状态的转变可能是由STAT3信号介导的。我们的研究提示FTY720可能是一种潜在的治疗脑炎症的药物，通过使慢性脑低灌注后的小胶质细胞向M2极化倾斜。
White matter (WM) ischemic injury, a major neuropathological feature of cerebral small vessel diseases, is an important cause of vascular cognitive impairment in later life. The pathogenesis of demyelination following WM ischemic damage are often accompanied by microglial activation. Fingolimod (FTY720) was approved for the treatment of multiple sclerosis for its immunosuppression property. In this study, we evaluated the neuroprotective potential of FTY720 in a WM ischemia model. Chronic WM ischemic injury model was induced by bilateral carotid artery stenosis (BCAS). Cognitive function, WM integrity, microglial activation and potential pathway involved in microglial polarization were assessed after BCAS. Disruption of WM integrity was characterized by demyelination in the corpus callosum and disorganization of Ranvier’s Nodes using Luxol Fast Blue staining, immunofluorescence staining and electron microscopy. In addition, radial maze test demonstrated that working memory performance was decreased at one-month post BCAS-induced injury. Interestingly, FTY720 could reduce cognitive decline and ameliorate the disruption of WM integrity. Mechanistically, cerebral hypoperfusion induced microglial activation, production of associated pro-inflammatory cytokines and priming of microglial polarization toward the M1 phenotype; whereas FTY720 attenuated microglia mediated neuroinflammation after WM ischemia and promoted oligodendrocytogenesis by shifting microglia toward M2 polarization. FTY720’s effect on microglial M2 polarization was largely suppressed by selective STAT3 blockade in vitro, revealing that FTY720-enabled shift of microglia from M1 to M2 polarization state was possibly mediated by STAT3 signaling. Our study suggested that FTY720 might be a potential therapeutic drug targeting brain inflammation by skewing microglia toward M2 polarization after chronic cerebral hypoperfusion.