Mdivi-1, a mitochondrial fission inhibitor, modulates T helper cells and suppresses the development of experimental autoimmune encephalomyelitis

• Main Authors: Yan-Hua Li, Fang Xu, Rodolfo Thome, Min-Fang Guo, Man-Luan Sun, Guo-Bin Song, Rui-lan Li, Zhi Chai, Bogoljub Ciric, A. M. Rostami, Mark Curtis, Cun-Gen Ma, Guang-Xian Zhang
• Format: Article
• Language: English
• Published: BMC 2019-07-01
• Series: Journal of Neuroinflammation
• Subjects: Experimental autoimmune encephalomyelitis; Dynamin-related protein 1; Mdivi-1; T cells
• Online Access: http://link.springer.com/article/10.1186/s12974-019-1542-0

Abstract Background Unrestrained activation of Th1 and Th17 cells is associated with the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). While inactivation of dynamin-related protein 1 (Drp1), a GTPase that regulates mitochondrial fission, can reduce EAE severity by protecting myelin from demyelination, its effect on immune responses in EAE has not yet been studied. Methods We investigated the effect of Mdivi-1, a small molecule inhibitor of Drp1, on EAE. Clinical scores, inflammation, demyelination and Drp1 activation in the central nervous system (CNS), and T cell responses in both CNS and periphery were determined. Results Mdivi-1 effectively suppressed EAE severity by reducing demyelination and cellular infiltration in the CNS. Mdivi-1 treatment decreased the phosphorylation of Drp1 (ser616) on CD4+ T cells, reduced the numbers of Th1 and Th17 cells, and increased Foxp3+ regulatory T cells in the CNS. Moreover, Mdivi-1 treatment effectively inhibited IFN-γ+, IL-17+, and GM-CSF+ CD4+ T cells, while it induced CD4+ Foxp3+ regulatory T cells in splenocytes by flow cytometry. Conclusions Together, our results demonstrate that Mdivi-1 has therapeutic potential in EAE by modulating the balance between Th1/Th17 and regulatory T cells.