脊髓水平外周Th17/Treg细胞迁移介导小胶质细胞极化在骨癌痛形成中的作用

Bone cancer induced pain is a formidable issue in clinical pain management. Recent studies have revealed that in several nervous system diseases, the involvement of peripheral T lymphocyte migration to CNS(central nervous system) as well as M1 phenotype polarization of microglia were observed. Peripheral T lymphocyte can enter into the CNS through defective BBB(blood brain barrier) and release abundant pro-inflammatory cytokines, followed by interaction with resident microglia and alteration of M1/M2 phenotypes of microglia. In our previous study, CD3+ T cell migration in the spinal level was observed in the bone cancer pain group. Accordingly, based on the establishment of bone cancer pain in C3H/HeN mouse model, this research aims to assess the types and time-course of T cell migrating in the spinal level, explore the mechanisms under T cell entering into the CNS, examine the alteration of Th17/Treg and M1/M2 phenotypes of microglia, and investigate the influence of inhibiting T cell entrance as well as regulating T cell phenotypes on bone cancer pain. This study will provide new thoughts for clinical intervention to bone cancer pain.

骨癌痛是临床疼痛治疗的一大难题。近期有研究表明，多种神经系统疾病与外周T淋巴细胞迁移及中枢水平小胶质细胞M1型极化相关。外周T淋巴细胞可通过病理状态下的血脑屏障进入中枢神经系统实质并释放促炎因子，改变中枢神经系统的免疫微环境，从而调控小胶质细胞M1/M2型极化的比例趋势。我们的前期研究发现，骨癌痛模型小鼠脊髓水平出现外周CD3+T淋巴细胞。据此，本项目拟应用C3H/HeN小鼠骨癌痛模型，检测外周T细胞迁移至脊髓的类型及时相变化，探讨T细胞侵入中枢的机制，并检测Th17/Treg和M1/M2型的变化，最后通过阻断T细胞进入中枢神经系统或对T细胞表型分化进行调控，探讨脊髓水平外周T淋巴细胞迁移介导的小胶质细胞极化在骨癌痛中的作用及相关机制，为临床防治骨癌痛提供新思路。

骨癌痛是临床疼痛治疗的一大难题。近期研究表明，多种神经系统疾病与外周T淋巴细胞迁移及中枢水平小胶质细胞M1型极化相关。外周T淋巴细胞可通过病理状态下的血脑屏障进入中枢神经系统实质并释放促炎因子，改变中枢神经系统的免疫微环境，从而调控小胶质细胞M1/M2型极化的比例趋势。我们前期研究发现，骨癌痛模型小鼠脊髓水平出现外周CD3+T淋巴细胞。本项目应用C3H/HeN小鼠骨癌痛模型，检测脊髓水平Th17/Treg和M1/M2型极化的改变，通过阻断T细胞进入中枢神经系统或对T细胞表型分化进行调控，深入探讨脊髓水平外周T淋巴细胞浸润的机制，及其介导的小胶质细胞极化在骨癌痛中的机制。研究结果显示：脊髓水平小胶质细胞和星形胶质细胞过度活化介导的炎症反应以及脊髓水平VEGFA-VEGFRs通路激活，引起血脊髓屏障完整性破坏，导致脊髓中出现CD3+CD4+ T细胞浸润，表现为Th17细胞进行性增多，而Treg细胞短暂表达后逐渐减少直至消失，Th17/Treg分化失衡；Th17细胞通过IL-17/IL-17A-IL-17AR通路作用于小胶质细胞，促进其向M1型极化，而M2型极化减少，导致失控的神经炎症反应；炎症介质诱导脊髓背角神经元出现持续的内质网应激PERK-eIF2α通路的激活，进而激活caspase-12、CHOP凋亡通路诱导神经元凋亡，共同导致骨癌痛的发生和进展。CB2受体激动剂通过减轻神经炎症反应，改善血脊髓屏障功能，减少T细胞浸润和减轻脊髓背角神经元内质网应激，显著缓解骨癌痛。本项目揭示了脊髓水平外周Th17/Treg细胞迁移介导小胶质细胞极化在骨癌痛中的作用机制，为临床防治骨癌痛提供了新的策略与理论依据。