Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, People's Republic of China.
Central Laboratory, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, People's Republic of China.
J Neuroinflammation. 2018 Feb 21;15(1):51. doi: 10.1186/s12974-018-1095-7.
With the recognition of the key roles of cellular metabolism in immunity, targeting metabolic pathway becomes a new strategy for autoimmune disease treatment. Guillain-Barré syndrome (GBS) is an acute immune-mediated inflammatory demyelinating disease of the peripheral nervous system, characterized by inflammatory cell infiltration. These inflammatory cells, including activated macrophages, Th1 cells, and Th17 cells, generally undergo metabolic reprogramming and rely mainly on glycolysis to exert functions. This study aimed to explore whether enhanced glycolysis contributed to the pathogenesis of experimental autoimmune neuritis (EAN), a classic model of GBS.
Preventive and therapeutic treatments with glycolysis inhibitor, 2-deoxy-D-glucose (2-DG), were applied to EAN rats. The effects of treatments were determined by clinical scoring, weighting, and tissue examination. Flow cytometry and ELISA were used to evaluate T cell differentiation, autoantibody level, and macrophage functions in vivo and in vitro.
Glycolysis inhibition with 2-DG not only inhibited the initiation, but also prevented the progression of EAN, evidenced by the improved clinical scores, weight loss, inflammatory cell infiltration, and demyelination of sciatic nerves. 2-DG inhibited the differentiation of Th1, Th17, and Tfh cells but enhanced Treg cell development, accompanied with reduced autoantibody secretion. Further experiments in vitro proved glycolysis inhibition decreased the nitric oxide production and phagocytosis of macrophages and suppressed the maturation of dendritic cells (DC).
The effects of glycolysis inhibition on both innate and adaptive immune responses and the alleviation of animal clinical symptoms indicated that enhanced glycolysis contributed to the pathogenesis of EAN. Glycolysis inhibition may be a new therapy for GBS.
随着人们认识到细胞代谢在免疫中的关键作用，靶向代谢途径成为治疗自身免疫性疾病的新策略。格林-巴利综合征（GBS）是一种急性免疫介导的炎症性脱髓鞘性周围神经病，其特征为炎症细胞浸润。这些炎症细胞，包括活化的巨噬细胞、Th1 细胞和 Th17 细胞，通常经历代谢重编程，并主要依赖糖酵解来发挥功能。本研究旨在探讨增强的糖酵解是否有助于实验性自身免疫性神经炎（EAN）的发病机制，EAN 是 GBS 的经典模型。
在 EAN 大鼠中应用糖酵解抑制剂 2-脱氧-D-葡萄糖（2-DG）进行预防和治疗。通过临床评分、称重和组织检查来评估治疗效果。流式细胞术和 ELISA 用于评估体内和体外 T 细胞分化、自身抗体水平和巨噬细胞功能。
用 2-DG 抑制糖酵解不仅抑制了 EAN 的起始，而且还阻止了其进展，这表现在临床评分、体重减轻、坐骨神经炎症细胞浸润和脱髓鞘的改善。2-DG 抑制了 Th1、Th17 和 Tfh 细胞的分化，但促进了 Treg 细胞的发育，同时减少了自身抗体的分泌。进一步的体外实验证明，糖酵解抑制降低了巨噬细胞的一氧化氮产生和吞噬作用，并抑制了树突状细胞（DC）的成熟。
糖酵解抑制对固有和适应性免疫反应的影响以及动物临床症状的缓解表明，增强的糖酵解有助于 EAN 的发病机制。糖酵解抑制可能是 GBS 的一种新疗法。
