IL4I1调控少突胶质祖细胞分化参与毛柳甙保护缺血性脑损伤的髓鞘再生机制

1. Remyelination plays a vital role in neural restoration. How to promote the differentiation of oligodendrocyte progenitor cells (OPCs) and remyelination is a challenge for stroke treatment. 2. Our previous study found that salidroside promoted OPC differentiation by regulation of microglia polarization, and thus promoted the neurological function after cerebral ischemia. We also found that the expression of IL4I1 was significantly up-regulated in cerebral ischemia treated with salidroside. A recent study reported that IL4I1 may promote remyelination, but its role and molecular mechanism after stroke have not been reported. 3. This project will use IL4I1-/- mice suffered from cerebral ischemia, primary cells co-cultured under oxygen glucose deprivation, laser capture microdissection technology and microfluidic cell culture systems. Our project would reveal the role of IL4I1 in cerebral ischemia treated with salidroside, and its effect on OPC differentiation and remyelination; reveal the role of IL4I1-STAT6 signaling mediated modulation of microglia polarization in OPC differentiation and remyelination after ischemic stroke treated with salidroside; confirm that the molecular mechanism of IL4I1-STAT3/STAT5 signaling mediated Treg differentiation in remyelination after ischemic stroke treated with salidroside. The aim of this project is to explore the new role and mechanism of IL4I1 in promoting remyelination after cerebral ischemia treated with salidroside, and provide a new theory for IL4I1 and salidroside in the treatment of ischemic stroke.

①髓鞘再生在神经损伤修复中发挥极其重要的作用。如何促进少突胶质祖细胞（OPC）分化和髓鞘再生是脑卒中治疗难题。②我们研究发现：毛柳甙干预小胶质细胞极化，促进OPC分化，从而促进脑缺血神经功能恢复；免疫调节酶IL4I1在毛柳甙治疗脑缺血中表达上调。最新研究显示，IL4I1可能促进髓鞘再生，但在中风中的作用及机制均未见报道。③本项目基于IL4I1-/-小鼠脑缺血模型和原代细胞氧糖剥夺模型，采用显微切割、微流控等技术，揭示IL4I1在脑缺血及毛柳甙治疗中，促进OPC分化及髓鞘形成中的作用；阐释毛柳甙治疗脑缺血中，IL4I1-STAT6通路调节小胶质细胞极化，对髓鞘再生的作用；探究脑缺血中，IL4I1-STAT3/STAT5通路介导Treg细胞分化在毛柳甙促进髓鞘再生中的分子机制。本项目旨在揭示IL4I1在毛柳甙促进脑缺血髓鞘再生中的新作用、新机制，为IL4I1及毛柳甙治疗缺血卒中提供新理论支持。

免疫炎症影响髓鞘再生，在白质损伤中发挥极其重要的作用。如何抑制炎症、促进髓鞘再生，从而维持白质完整性是卒中治疗难题。本项目研究发现：①免疫调节酶IL4I1在短暂性脑缺血急性期迅速下降，慢性期逐渐向正常水平恢复，并且IL4I1在毛柳甙治疗脑缺血中表达上调；②毛柳甙干预小胶质细胞极化，促进少突胶质祖细胞增殖分化，从而促进脑缺血神经功能恢复和认知功能改善；③在短暂性脑缺血中，与野生型小鼠相比， IL4I1-/-小鼠生存率下降，感觉运动神经功能受损，脑梗死体积增大，学习记忆功能下降；④同样在永久性脑缺血模型中，IL4I1-/-小鼠运动及认知功能下降，脑梗死体积增大；⑤确定重组IL4I1经鼻腔给药最佳剂量，永久性脑缺血野生小鼠连续给予IL4I1，可明显改善神经功能，减小脑梗死体积；⑥IL4I1-/-促进脑缺血小鼠小胶质细胞由M1促炎表型向M2抗炎表型转化，调节缺血脑组织中CD4+T细胞向Treg细胞分化，并抑制Th17细胞数量；⑦经电镜和DTI证实IL4I1-/-小鼠在脑缺血恢复期髓鞘完整性下降，野生型小鼠经鼻给予IL4I1并可促进白质纤维修复及少突胶质祖细胞增殖；⑧短暂性脑缺血皮层转录组学分析显示IL4I1敲除显著下调的Ikbkg基因，以及通过KEGG及GSEA分析出与Ikbkg显著相关的PD-L1信号通路与C型凝集素受体信号通路。本项目揭示IL4I1在毛柳甙促进脑缺血髓鞘再生中的新作用、并揭示了IL4I1在脑缺血及毛柳甙治疗脑缺血中对小胶质细胞介导的炎症和白质完整性中的作用机制，为IL4I1及毛柳甙治疗缺血性卒中提供新的理论支持和转化前景。