Guo Min-Fang, Meng Jian, Li Yan-Hua, Yu Jie-Zhong, Liu Chun-Yun, Feng Ling, Yang Wan-Fang, Li Jun-Lian, Feng Qian-Jin, Xiao Bao-Guo, Ma Cun-Gen
Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China.
Department of Encephalopathy and National Major Clinical Department of Ministry of Health, Third Hospital, Department of Neurology, Shanxi University of Traditional Chinese Medicine, Taiyuan, China.
J Neurol Sci. 2014 Aug 15;343(1-2):69-75. doi: 10.1016/j.jns.2014.05.034. Epub 2014 May 27.
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases characterized by the immune-mediated demyelination and neurodegeneration of the CNS. Our previous studies showed that Rho kinase inhibitor Fasudil can delay onset, and ameliorate severity of EAE, accompanied by the improvement in myelination and the inhibition of inflammatory responses in the CNS. In this study, we found that Fasudil inhibited the migration of T cells indirectly by affecting the production of inflammatory factors and the expression of chemokines in astrocytes functions, indicating that Fasudil treatment reduced inflammatory cytokines such as TNF-α and IL-6, reactive oxygen species (NO) and chemokines like MIP-3α (CCL-20), RANTES (CCL5), MIP-1α (CCL-3) and MCP-1 (CCL2) in vitro, and blocked the chemotaxis of reactive mononuclear cells in EAE mice. Further studies found that Fasudil treatment reduced the infiltration and accumulation of pathogenic T cells into the CNS. Astrocytes expressing GFAP and CCL-20 were inhibited in Fasudil-treated EAE compared with control mice. These results demonstrate that Fasudil alleviates the pathogenesis of EAE possibly by blocking astrocyte-derived chemokine-mediated migration of inflammatory macrophages and pathogenic T cells, and might be used to treat MS.
多发性硬化症（MS）及其动物模型实验性自身免疫性脑脊髓炎（EAE）是自身免疫性疾病，其特征在于中枢神经系统的免疫介导的脱髓鞘和神经变性。我们之前的研究表明，Rho激酶抑制剂法舒地尔可以延迟EAE的发病并减轻其严重程度，同时伴有髓鞘形成的改善和中枢神经系统炎症反应的抑制。在本研究中，我们发现法舒地尔通过影响星形胶质细胞功能中炎性因子的产生和趋化因子的表达间接抑制T细胞迁移，这表明法舒地尔治疗在体外可降低炎性细胞因子如TNF-α和IL-6、活性氧（NO）以及趋化因子如MIP-3α（CCL-20）、RANTES（CCL5）、MIP-1α（CCL-3）和MCP-1（CCL2），并阻断EAE小鼠中反应性单核细胞的趋化作用。进一步研究发现，法舒地尔治疗可减少致病性T细胞向中枢神经系统的浸润和积聚。与对照小鼠相比，在法舒地尔治疗的EAE中，表达GFAP和CCL-20的星形胶质细胞受到抑制。这些结果表明，法舒地尔可能通过阻断星形胶质细胞衍生的趋化因子介导的炎性巨噬细胞和致病性T细胞迁移来减轻EAE的发病机制，并且可能用于治疗MS。
