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The inhibition of Rho kinase blocks cell migration and accumulation possibly by challenging inflammatory cytokines and chemokines on astrocytes

  • Min-Fang Guo
    Affiliations
    Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China
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  • Jian Meng
    Affiliations
    Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China
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  • Yan-Hua Li
    Affiliations
    Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China
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  • Jie-Zhong Yu
    Affiliations
    Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China
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  • Chun-Yun Liu
    Affiliations
    Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China
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  • Ling Feng
    Affiliations
    Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China
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  • Wan-Fang Yang
    Affiliations
    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
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  • Jun-Lian Li
    Affiliations
    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
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  • Qian-Jin Feng
    Affiliations
    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
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  • Bao-Guo Xiao
    Correspondence
    Corresponding author. Tel.: +86 351 2272208, +86 18203515288 (Mobile); fax: +86 351 2272696.
    Affiliations
    Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China
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  • Cun-Gen Ma
    Correspondence
    Correspondence to: C.-G. Ma, Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China. Tel.: +86 351 2272208, +86 18203515288 (Mobile); fax: +86 351 2272696.
    Affiliations
    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
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      Highlights

      • Fasudil reduces inflammatory cytokines and chemokines in cultured astrocytes.
      • Fasudil reduces infiltration and accumulation of pathogenic T cells into the CNS.
      • The expression of CCL-20 on astrocytes was inhibited in Fasudil-treated EAE.
      • Fasudil declines astrocyte chemokine-mediated infiltration of pathogenic T cells.

      Abstract

      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.

      Keywords

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