星形胶质细胞来源的HMGB1参与实验性自身反应性脑脊髓炎的机制

Astrocyte is the major cell type that constructs the blood-brain barrier (BBB) and neurovascular unit. How astrocyte maintains the immunologic homeostasis in the central nervous system (CNS) is still a puzzle. The pre-limitary data of applicant indicate that astrocyts express high mobility group box 1 (HMGB1) which is dynamic changed and plays key roles in the experimental autoimmune encephalomyelitis. However the mechanism needs to be addressed. The function of HMGB1 is usually determined by its cellular and subcellular location. We propose that HMGB1 in the nuclear of astrocyte takes part in the maintaining of integrity of BBB endothelium, decreases the permeability of BBB, and prevents the activated immune cells migration to CNS. Meanwhile, the HMGB1 released out of astrocytes is heterogeneity based on structure and function. The redox and post-translation modification of HMGB1 is involved in the development and remission of EAE. In this proposal, we are going to breed the astrocyte specific HMGB1 knock-out mice, and use immunological and neurological methods toinvestigate the effects of nuclear HMGB1, as well as redox and post-translation modification of HMGB1 derived from astrocytes on BBB and the cell components in neurovascular unit in vivo and in vitro respectively. The result will discover the immune releated characteristics of astrocytes, and resolve the cells and molecules network involved in the initiation, development and remission of autoimmune encephalomyelitis and supply more new clues and targets for the prevention and treatment of multiple sclerosis.

星形胶质细胞是构成血脑屏障和神经血管单元的关键细胞，其维持神经中枢免疫稳态的机制尚有许多未解之谜。申请者前期研究发现星形胶质细胞表达警报素分子HMGB1（高迁移率族蛋白1），在实验性自身反应性脑脊髓炎（EAE)中存在动态变化并发挥关键作用，但作用机制尚待深入研究。由于HMGB1的功能与其细胞定位和亚细胞定位直接相关，本项目推测：星形胶质细胞核内HMGB1通过直接调控Shh（音猥因子）信号通路参与维持血脑屏障血管内皮完整性，低通透性和阻止活化免疫细胞浸润神经中枢；而胞外HMGB1结构与功能具有异质性，通过发生氧化还原状态和翻译后修饰变化参与炎症的发展或消退。本项目将繁育星形胶质细胞特异性Hmgb1敲除鼠，利用免疫学和神经学方法，通过体内外实验探讨星形胶质细胞内、外HMGB1参与EAE发生、发展和缓解的细胞和分子机制，为防治多发性硬化提供新的线索和靶标.

星形胶质细胞是构成血脑屏障和神经血管单元的关键细胞，其维持神经中枢免疫稳态的机制尚有许多未解之谜。申请者前期研究发现星形胶质细胞表达警报素分子HMGB1（高迁移率族蛋白1），在实验性自身反应性脑脊髓炎（EAE)中存在动态变化并发挥关键作用，但作用机制尚待深入研究。本项目成功繁育了星形胶质细胞特异性Hmgb1敲除鼠，制备了主动EAE小鼠模型，利用免疫学和神经学方法，通过体内外实验探讨了星形胶质细胞来源的HMGB1参与EAE发生、发展和缓解的细胞和分子机制。研究结果显示在体敲除星形胶质细胞来源的HMGB1可通过降低血脑屏障通透性、减少中枢炎性细胞浸润、减弱小胶质细胞活化、减少A1型星形胶质细胞等机制最终减轻EAE的症状和脱髓鞘表现。而外源性给予甘草甜素抑制HMGB1的功能可显著抑制EAE小鼠星形胶质细胞和小胶质细胞的活化及减轻神经元损伤，显著抑制HMGB1在中枢神经系统的表达和释放，显著减轻EAE小鼠神经中枢的炎症、脱髓鞘和炎症细胞浸润，进而有效缓解小鼠的EAE。证明了星形胶质细胞来源的HMGB1在自身免疫性脑脊髓炎发生发展中的重要作用，而针对星形胶质细胞来源的HMGB1进行干预可用于治疗多发性硬化，甘草甜素是有价值的候选药物。