Fasudil mediates cell therapy of EAE by immunomodulating encephalomyelitic T cells and macrophages

• Published in: European journal of immunology Vol. 45; no. 1; pp. 142 - 152
• Main Authors: Liu, Chun‐Yun, Guo, Shang‐De, Yu, Jie‐Zhong, Li, Yan‐Hua, Zhang, Hui, Feng, Ling, Chai, Zhi, Yuan, Hai‐Jun, Yang, Wan‐Fang, Feng, Qian‐Jin, Xiao, Bao‐Guo, Ma, Cun‐Gen
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.01.2015
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; Animals; Arginase - genetics; Arginase - immunology; Cell- and Tissue-Based Therapy; Chemokine CCL20 - genetics; Chemokine CCL20 - immunology; Encephalomyelitis, Autoimmune, Experimental - chemically induced; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Encephalomyelitis, Autoimmune, Experimental - therapy; Experimental autoimmune encephalomyelitis; Fasudil; Female; Gene Expression Regulation; Immunomodulation - drug effects; Interleukin-10 - genetics; Interleukin-10 - immunology; Interleukin-12 - genetics; Interleukin-12 - immunology; Lymphocytes; Macrophage polarization; Macrophages - drug effects; Macrophages - immunology; Medical research; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - immunology; Peptide Fragments; Primary Cell Culture; Receptors, IgG - genetics; Receptors, IgG - immunology; Rho kinase inhibitor; Signal Transduction; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - transplantation; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; Transcription Factor RelA - genetics; Transcription Factor RelA - immunology; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - immunology; T‐cell regulation; Experimental autoimmune encephalomyelitis; Rho kinase inhibitor; Macrophage polarization; T-cell regulation; Fasudil
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201344429

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.