SDF-1/CXCR4信号通路在NMO-IgG介导的炎性脱髓鞘视神经炎中促进髓鞘修复的作用及机制研究

Optic neuritis (ON) is one of the most common ophthalmological diseases, which mostly occurs in young adults and the middle aged. ON always occur as the first symptom of neuromyelitis optica (NMO) in Asia. Neuromyelitis optica is an inflammatory demyelinating disorder of the CNS. Failure of axon ensheathment and loss of neural function are extensively observed in NMO lesions due to a loss of oligodendrocytes. Remyelination failure may be attributed to impaired recruitment and arrested differentiation of endogenous OPCs. It is reported that modulating the SDF-1/CXCR4 chemokine axis during the pathological process might benefit remyelination by enhancing OPC recruitment and differentiation. Our recent study has demonstrated that NMOSD patients with a lower CSF level of SDF-1 and higher AQP4 autoantibody level usually had a poor recovery after treatment when compared with those with higher SDF-1 level. Using SDF-1 and the CXCR4 antagonist AMD3100, combined with in vitro cell research, this study intends to evaluate rats’ motor function, demyelinated histopathological features and cellular and molecular biologic changes. The aim of this study is to understand the mechanisms responsible for repair of damaged myelin, which is critical for developing therapies that promote remyelination and prevent disease progression.

视神经炎（ON）是中青年人主要致盲性眼病，与视神经脊髓炎（NMO）密切相关。促进病灶处髓鞘的修复及再生是治疗疾病和改善预后的关键，而SDF-1/CRCX4信号通路是调控髓鞘修复再生的重要通路。我们前期临床研究发现，脑脊液中SDF-1浓度与NMO相关视神经炎患者预后密切相关；通过我们创新性动物模型研究发现，该信号通路参与调控NMO炎性脱髓鞘病变髓鞘修复再生。我们认为SDF-1/CXCR4信号通路是通过调控少突胶质前体细胞(OPCs)的存活、迁移、增殖及分化过程来促进髓鞘修复再生，但具体作用机制尚不明确。本研究首次研究SDF-1/CXCR4信号通路在NMO-IgG诱导的炎性脱髓鞘病灶中的调控作用机制，拟从动物实验及细胞实验两方面，进一步证实其在NMO炎性脱髓鞘病变中的作用，明确其调控OPCs的作用机制；探索CNS炎症诱导局部髓鞘修复的起点及下游信号通路，具有较好的科学创新性和显著临床应用价值。

视神经炎是青中年人最易罹患的致盲性视神经疾病，在亚洲人种中以视神经脊髓炎相关视神经炎(NMO-ON)发病率最高，主要由致病性自身抗体NMO-IgG导致炎症性脱髓鞘病灶所致。髓鞘再生是脱髓鞘性视神经炎的重要修复方式，促进病灶处髓鞘的修复及再生成为治疗疾病、改善预后的关键。本研究通过鞘内重复注射人源性NMO-IgG和人补体的方法成功建立脊髓NMO病灶的大鼠模型，模拟人NMO炎性脱髓鞘病变特征，以研究SDF-1/CXCR4信号通路在炎性脱髓鞘病灶发展过程中对髓鞘修复的调控作用；同时结合体外培养大鼠少突胶质前体细胞（Oligodendrocyte precursor cells, OPCs），明确SDF-1/CXCR4信号通路对OPCs的调控方式及下游信号通路。研究发现，SDF-1/CXCR4信号通路的激活对局部炎症性脱髓鞘病灶起保护性作用，可促进炎性脱髓鞘病灶髓鞘修复：动物脱髓鞘病灶所致的症状减轻，行为学评分降低；组织病理学结果显示AQP4丢失减少，星形胶质细胞损伤减轻，局部炎症细胞浸润程度减轻，局部OPCs细胞增殖、分化增多，脱髓鞘病灶面积减小。体外细胞实验证实SDF-1/CXCR4信号通路可通过调控OPCs的迁移、增殖及分化形成成熟的少突胶质细胞以完成髓鞘修复的功能。本研究结合动物实验及细胞实验，发现SDF-1/CXCR4信号通路在NMO-IgG诱导的炎性脱髓鞘病灶中对髓鞘修复的促进作用，为未来视神经炎治疗新方法研究提供了依据。