Treg/Th17失衡介导的神经炎症在帕金森病发病机制中的作用

Neuroinflammation has been presented as a new pathogenesis of Parkinson's disease (PD) in recent decade. Regulatory T (Treg) cells and helper T 17 (Th17) cells are two recently found subsets of CD4+ T lymphocytes. Treg cells have immunosuppressive effect and Th17 cells are pro-inflammatory. However, roles of Treg and Th17 cells in pathogenesis of PD and mechanisms underlying the roles are less clear. In our recent pre-experiments, we observed that the blood-brain barrier was damaged in the substantia nigra of MPTP-induced mice model of Parkinson's disease (PD), and CD4+ T cells were permeated into the brain tissue, suggesting that CD4+ T cells are implicated in PD neuroinflammation. On the basis of the facts, in the present project, first, we provide the evidence that there is an imbalance in number and function of Treg/Th17 cells in PD brain, which leads to neuroinflammation and therefore induces and aggravates PD. Then, using MPP+-induced PD model in vitro, we explore pathways by which Treg and Th17 affect dopaminergic neurons. A mediation via microglia and a direct action on neurons are both involved in the Treg and Th17 action pathways. Treg cells decrease microglial inflammatory reaction and protect doperminergic neurons by mechanisms of secreting anti-inflammatory cytokines and activatig receptors on the microglial cells and neurons. Th17 cells enhance microglial inflammatory reaction and injure doperminergic neurons by the action of pro-inflammatory cytokines on receptors on the microglial cells and neurons. Subsequently, a mechanism via cell-cell contact communication between Treg/Th17 cells and neurons is also revealed to be implicated in the effects of Treg and Th17 cells on PD dopaminergic neurons. The mechanisms are related to CD47-SIRPA signaling pathway for Treg cells and neurons, and to Fas/FasL pathway for neurons/Th17 cells. Lastly, by means of adoptive transfer of Treg cells into PD model mice, we demonstrate that the therapy facilitates Treg/Th17 balance in the brain, alleviates neuroinflammation, and therefore improves PD in the symptom and pathology. These studies provide a rationale basis for better understanding of PD pathogenesis and for designing new therapeutic strategies of PD.

神经炎症作为帕金森病（PD）的发病机制是近10多年来的新发现。具有免疫抑制性的Treg细胞和具有致炎作用的Th17细胞是CD4+T细胞家族中的新成员。我们前期研究观察到，MPTP诱导的PD模型小鼠黒质中血脑屏障破坏、CD4+T细胞渗入脑实质。据此，本项目首先研究渗入到脑内的CD4+T细胞中Treg减少/Th17增加的失衡导致了神经炎症，诱发和加重PD；接着利用MPP+诱导的PD体外模型，探讨Treg和Th17经分泌细胞因子作用于受体来影响PD小胶质细胞的炎症反应和多巴胺能神经元的存亡；继而揭示Treg经CD47-SIRPA和Th17经Fas/FasL的细胞间直接接触机制对PD的多巴胺能神经元产生保护或毒性作用；最后将Treg细胞过继转移给PD小鼠，观察通过促进脑内Treg/Th17平衡来减轻神经炎症，改善PD运动功能和病理变化。为临床上进一步了解PD发病机制及设计防治PD的新策略提供资料。

研究背景和内容：帕金森病（Parkinson’s disease，PD）是一种慢性、进行性神经系统退行性疾病，其基本病理特征是中脑黑质中多巴胺能神经元的变性缺失，临床表现为静止性震颤、运动迟缓、肌强直和姿势步态异常等。PD的病因及发病机制尚未完全明了，PD也不能完全治愈。近10多年研究发现，神经炎症参与了PD的发病机制，但这些研究主要集中在脑内小胶质细胞激活介导的神经炎症的作用。本项目研究T淋巴细胞的两种较新亚群Treg细胞和Th17细胞失衡介导的神经炎症在PD中的作用及其机制，并探讨纠正Treg/Th17失衡对PD的治疗作用。.重要结果和数据：在PD模型小鼠的中脑黑质中，血脑屏障破坏、Th17细胞增加、Treg细胞减弱，这种Th17/Treg失衡导致了PD的神经炎症。Treg细胞释放的抗炎细胞因子TGF-β1以及Th17细胞释放的促炎细胞因子IL-17A对多巴胺能神经元没有直接的保护或损伤作用，而是这些细胞因子作用于小胶质细胞上的相应受体抑制或促进小胶质细胞的过度激活从而发挥保护或损伤多巴胺能神经元的作用。Treg细胞膜上的配体CD47与多巴胺能神经元膜上的受体SIRPA的相互作用介导了Treg细胞对多巴胺能神经元的细胞接触保护；Th17细胞膜上的粘附分子LFA-1与多巴胺能神经元膜上的粘附分子ICAM-1的相互作用介导了Th17细胞对多巴胺能神经元的细胞接触损伤。Treg细胞过继转移能抑制PD脑内Th17/Treg失衡介导的神经炎症并减轻PD的症状和病理学表现。.科学意义：本项目结果提出了新的见解，即：除了小胶质细胞介导的神经炎症以外，PD脑内也出现Th17/Treg失衡介导的神经炎症，但Treg细胞和Th17细胞释放的细胞因子对多巴胺能神经元没有或者很少产生直接的作用，而是通过小胶质细胞的介导，这些细胞因子对多巴胺能神经元发挥间接作用，然而，Treg细胞和Th17细胞都能借助于膜表面分子的相互作用直接地接触多巴胺能神经元发挥其神经保护或神经损伤的作用，因此Treg细胞过继转移能减轻PD的症状及病理学表现。这些原创性的结果和见解为T细胞诱导的适应性免疫反应在PD脑内的作用及作用方式提供了全新的观点，也为PD的治疗策略提供潜在的免疫治疗前景。