title: Fasudil mediates cell therapy of EAE by immunomodulating encephalomyelitic T cells and macrophages.
abstract: Although Fasudil has shown therapeutic potential in EAE mice, the mechanism of action are still not fully understood. Here, we examined the immunomodulatory effect of Fasudil on encephalitogenic mononuclear cells (MNCs), and tested the therapeutic potential of Fasudil-treated MNCs in active EAE. Fasudil inhibited expression of CCL20 on T cells and migration of T cells, decreased CD4(+) IFN-γ(+) and CD4(+) IL-17(+) T cells, but increased CD4(+) IL-10(+) and CD4(+) TGF-β(+) T cells. Fasudil reduced expression of CD16/32 and IL-12, while elevating expression of CD206, CD23, and IL-10. Fasudil also decreased levels of iNOS/NO, enhanced levels of Arg-1, and inhibited the TLR-4/NF-κB signaling and TNF-α, shifting M1 macrophage to M2 phenotype. These modulatory effects of Fasudil on T cells and macrophages were not altered by adding autoantigen MOG35-55 to the culture, i.e., autoantigen-independent. Further, we observed that, in vitro, Fasudil inhibited the capacity of encephalitogenic MNCs to adoptively transfer EAE and reduced TLR-4/p-NF-κB/p65 and inflammatory cytokines in spinal cords. Importantly, Fasudil-treated encephalitogenic MNCs exhibited therapeutic potential when injected into actively induced EAE mice. Together, our results not only provide evidence that Fasudil mediates the polarization of macrophages and the regulation of T cells, but also reveal a novel strategy for cell therapy in MS.
authors.affiliation: Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China.
authors.forename: Chun-Yun
authors.initials: CY
authors.lastname: Liu
authors.forename: Shang-De
authors.initials: SD
authors.lastname: Guo
authors.forename: Jie-Zhong
authors.initials: JZ
authors.lastname: Yu
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Feng
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chai
authors.forename: Hai-Jun
authors.initials: HJ
authors.lastname: Yuan
authors.forename: Wan-Fang
authors.initials: WF
authors.lastname: Yang
authors.forename: Qian-Jin
authors.initials: QJ
authors.lastname: Feng
authors.forename: Bao-Guo
authors.initials: BG
authors.lastname: Xiao
authors.forename: Cun-Gen
authors.initials: CG
authors.lastname: Ma
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001119:Arginase / Q000235:genetics / Q000276:immunology; D064987:Cell- and Tissue-Based Therapy; D054418:Chemokine CCL20 / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D005260:Female; D005786:Gene Expression Regulation; D056747:Immunomodulation / Q000187:drug effects*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments; D061251:Primary Cell Culture; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology
chemical_list: C493447:CCL20 protein, mouse; D054418:Chemokine CCL20; C499172:Fcgr2b protein, mouse; C485700:Fcgr3 protein, mouse; C556062:IL10 protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D017452:Receptors, IgG; C498144:Rela protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; C445081:myelin oligodendrocyte glycoprotein (35-55); D016753:Interleukin-10; D018664:Interleukin-12; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C544448:Arg1 protein, mouse; D001119:Arginase; C049347:fasudil
keywords: Experimental autoimmune encephalomyelitis; Fasudil; Macrophage polarization; Rho kinase inhibitor; T-cell regulation