Abstract
We observed the therapeutic effect of Fasudil and explored its mechanisms in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Fasudil, a selective Rho kinase (ROCK) inhibitor, was injected intraperitoneally at 40 mg/kg/d in early and late stages of EAE induction. Fasudil ameliorated the clinical severity of EAE at different stages, and decreased the expression of ROCK-II in spleen, accompanied by an improvement in demyelination and inhibition of inflammatory cells. Fasudil mainly inhibited CD4+IL-17+ T cells in early treatment, but also elevated CD4+IL-10+ regulatory T cells and IL-10 production in late treatment. The treatment of Fasudil shifted inflammatory M1 to anti-inflammatory M2 macrophages in both early and late treatment, being shown by inhibiting CD16/32, iNOS, IL-12, TLR4 and CD40 and increasing CD206, Arg-1, IL-10 and CD14 in spleen. By using Western blot and immunohistochemistry, iNOS and Arg-1, as two most specific markers for M1 and M2, was inhibited or induced in splenic macrophages and spinal cords of EAE mice treated with Fasudil. In vitro experiments also indicate that Fasudil shifts M1 to M2 phenotype, which does not require the participation or auxiliary of other cells. The polarization of M2 macrophages was associated with the decrease of inflammatory cytokine IL-1β, TNF-α and MCP-1. These results demonstrate that Fasudil has therapeutic potential in EAE possibly through inducing the polarization of M2 macrophages and inhibiting inflammatory responses.
Highlights
Multiple sclerosis (MS) is an immune-mediated chronic inflammatory demyelinating disease of the central nervous system (CNS), destroying the myelin and the axon in variable degrees
Previous studies have demonstrated that Fasudil ameliorated severity of EAE partly by decreasing blood brain barrier (BBB) permeability [31] and inflammatory cell infiltration in the CNS [32,33]
In SJL/J mice induced with PLP139–151, Fasudil reduced the proliferation of specific T cells, together with a down-regulation of IL-17 and a decrease of the IFN-c/IL-4 ratio [32]
Summary
Multiple sclerosis (MS) is an immune-mediated chronic inflammatory demyelinating disease of the central nervous system (CNS), destroying the myelin and the axon in variable degrees. The etiology of MS is still not known, a combination of several factors may be involved, including genetics, environment, and possibly a virus [1]. The pathogenesis of MS may be related to activation, migration and effector function of immune cells as well as their products such as cytokines, chemokines, adhesion molecules or other inflammatory factors [5,6,7]. These constitute the modern immunological basis for the development of novel clinical and preclinical immunomodulatory therapies for MS [8]
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