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

Yan-Hua Li,Rui-Lan Li,Rodolfo Thome,Cun-Gen Ma,Guo-Bin Song,Fang Xu,Min-Fang Guo,Mark Curtis,Zhi Chai,Man-Luan Sun,Guang-Xian Zhang,A M Rostami,Bogoljub Ciric

doi:10.1186/s12974-019-1542-0

Abstract

BackgroundUnrestrained 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.MethodsWe 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.ResultsMdivi-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.ConclusionsTogether, our results demonstrate that Mdivi-1 has therapeutic potential in EAE by modulating the balance between Th1/Th17 and regulatory T cells.

Highlights

Multiple sclerosis (MS) is an immune-mediated chronic demyelinating disease of the central nervous system (CNS), characterized by inflammatory infiltrates, myelin loss, and axonal damage [17, 23]
Mitochondrial division inhibitor-1 (Mdivi-1) alleviated the severity of EAE To investigate if Mdivi-1 suppresses EAE, mice were immunized with MOG35–55 peptide and treated with daily doses of Mdivi-1 (25 mg/kg) or vehicle (DMSO 0.1%) from day 3 p.i. until day 27 p.i
These results show that, Mdivi-1 does not influence the onset of EAE, overall demyelination and clinical development were reduced in treated mice compared with controls

Summary

Introduction

Multiple sclerosis (MS) is an immune-mediated chronic demyelinating disease of the central nervous system (CNS), characterized by inflammatory infiltrates, myelin loss, and axonal damage [17, 23]. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that is often used to study the pathogenesis and therapeutics of the disease. Treatment with P110, a peptide inhibitor that targets dynamin-related protein 1 (Drp1), protects myelin in cuprizone-induced demyelination and EAE models by blocking Drp localization to the mitochondria, reducing mitochondrial fragmentation, oligodendroglial. 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

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Conclusion