蛋氨酸亚砜还原酶A负性调控氧化应激及小胶质细胞炎性激活在实验性自身免疫性脑脊髓炎中的作用及其机制

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and experimental autoimmune encephalomyelitis (EAE) has been widely recognized as an ideal animal model of MS due to their similar pathological features and clinical manifestations. CD4+ T cell-mediated autoimmune response plays a central role in the pathological process of EAE/MS. Meanwhile, overactivated microglia and reactive oxygen species (ROS) can be directly or indirectly involved in regulating the activation, proliferation and differentiation of pathologic CD4+ T cell by many means, thereby aggravating the severity of EAE/MS. Therefore, inhibition of microglial overactivation and antioxidant therapy have become promising research directions for the treatment of MS. Methionine residues on proteins serve as a pivotal antioxidant defense that protects proteins against oxidative stress, nonetheless, their role in EAE/MS remains virtually unknown. As a key enzyme controlling the cyclic oxidation/reduction of methionine, MsrA has been confirmed to scavenge ROS and alleviate microglia-mediated neuroinflammation. Therefore, the aim of this term is to further explore the role of MsrA-catalytic methionine antioxidant defense in EAE/MS and its mechanisms. Our findings may supply experimental data for the development of novel drugs to treat MS and other autoimmune diseases.

多发性硬化（MS）是一种发生于中枢神经系统的自身免疫性疾病。实验性自身免疫性脑脊髓炎（EAE）由于与MS具有相似的病理特征及临床表现，已被国际公认为是MS相关研究的理想动物模型。CD4+ T细胞所介导的自身免疫反应在EAE/MS的病理进程中处于核心地位，而过度激活的小胶质细胞和氧自由基（ROS）已被证实可通过多种途径参与调控CD4+ T细胞的异常活化。因此，减缓氧化应激、抑制小胶质细胞炎性活化已成为新型MS治疗药物开发的重要研究方向。蛋氨酸亚砜还原酶A（MsrA）是体内调控蛋氨酸抗氧化防御体系的关键酶，其在EAE/MS中所扮演的角色尚不清楚。申请者在最新发表的研究成果中已证实：MsrA可直接清除ROS并进而抑制小胶质细胞所介导的神经炎症，因此，本项目旨在进一步探索MsrA在EAE/MS中的作用，并试图从小胶质细胞炎性激活及氧化应激等角度阐明机制，为以MsrA为靶点开发相关新药提供实验依据。

多发性硬化（multiple sclerosis，MS）是一种发生于中枢神经系统的自身免疫性疾病，至今仍无法治愈。活性氧（reactive oxygen species，ROS）和过度激活的小胶质细胞可通过多种途径参与调控CD4+ T细胞的异常活化并进而加剧MS的发生及发展，因此，减缓氧化应激、抑制小胶质细胞炎性活化已成为新型MS治疗药物开发的重要研究方向。蛋氨酸亚砜还原酶A（Methionine sulfoxide reductase A，MsrA）是体内调控蛋氨酸抗氧化防御体系的关键酶，我们的前期研究结果显示MsrA可通过催化 ROS 氧化蛋氨酸生成蛋氨酸亚砜的反应而直接清除 ROS，并进一步通过抑制“ROS/MAPKs/NF-κB”信号级联反应而减缓小胶质细胞的炎性激活。在本研究中，我们进一步利用实验性自身免疫性脑脊髓炎（experimental autoimmune encephalomyelitis，EAE）动物模型对MsrA在MS/EAE中的作用及其机制进行系统研究。我们发现：通过MsrA过表达腺相关病毒外源性上调MsrA的表达水平可显著降低EAE小鼠的发病率并改善其临床神经功能表现；此外，MsrA还可明显缓解EAE小鼠髓鞘脱失、炎性细胞浸润、轴索损伤等典型组织病理学改变；进一步的机制研究表明MsrA的上述保护作用主要是通过抑制EAE小鼠体内过度积累的ROS以及炎性激活的小胶质细胞，从而减缓CD4+ T细胞的Th1/Th17促炎性分化并促进其Th2抗炎性分化实现的。上述研究结果为MS的防治提供了新的治疗靶点和实验依据。