Mdivi-1，一种线粒体分裂抑制剂，调节辅助性 T 细胞并抑制实验性自身免疫性脑脊髓炎的发展。

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

机构信息

Department of Neurology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.

Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong, 037009, China.

出版信息

J Neuroinflammation. 2019 Jul 19;16(1):149. doi: 10.1186/s12974-019-1542-0.

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.

背景

Th1 和 Th17 细胞的不受控制的激活与多发性硬化症及其动物模型实验性自身免疫性脑脊髓炎（EAE）的发病机制有关。虽然抑制动力相关蛋白 1（Drp1）的失活，一种调节线粒体裂变的 GTPase，可以通过保护髓磷脂免受脱髓鞘来减轻 EAE 的严重程度，但它对 EAE 中的免疫反应的影响尚未被研究。

方法

我们研究了 Drp1 的小分子抑制剂 Mdivi-1 对 EAE 的影响。确定了中枢神经系统（CNS）中的临床评分、炎症、脱髓鞘和 Drp1 激活，以及 CNS 和外周血中的 T 细胞反应。

结果

Mdivi-1 通过减少中枢神经系统中的脱髓鞘和细胞浸润，有效抑制 EAE 的严重程度。Mdivi-1 治疗降低了 CD4 T 细胞中 Drp1（ser616）的磷酸化，减少了 Th1 和 Th17 细胞的数量，并增加了 CNS 中的 Foxp3 调节性 T 细胞。此外，Mdivi-1 治疗通过流式细胞术有效抑制了 IFN-γ、IL-17 和 GM-CSF CD4 T 细胞，同时诱导了脾细胞中的 CD4 Foxp3 调节性 T 细胞。