Fasudil mediates cell therapy of EAE by immunomodulating encephalomyelitic T cells and macrophages |
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Authors: | Chun‐Yun Liu Shang‐De Guo Jie‐Zhong Yu Yan‐Hua Li Hui Zhang Ling Feng Zhi Chai Hai‐Jun Yuan Wan‐Fang Yang Qian‐Jin Feng Bao‐Guo Xiao Cun‐Gen Ma |
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Institution: | 1. Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China;2. “2011” Collaborative Innovation Center/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;3. Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China |
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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. |
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Keywords: | Experimental autoimmune encephalomyelitis Fasudil Macrophage polarization Rho kinase inhibitor T‐cell regulation |
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