School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518055, Guangdong, China.
School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518055, Guangdong, China.
Int Immunopharmacol. 2023 Mar;116:109717. doi: 10.1016/j.intimp.2023.109717. Epub 2023 Feb 2.
Multiple sclerosis is a chronic demyelinating autoimmune disease accompanied by inflammation and loss of axons and neurons. Toll-like receptors play crucial roles in the innate immune system and inflammation. However, few studies have explored the specific effects of toll-like receptor 7 signaling pathway in multiple sclerosis. To explore underlying effects to develop a new therapeutic target, we use Vesatolimod, a safe and well-tolerated agonist of toll-like receptor 7, to assess the possible effects in Experimental autoimmune encephalomyelitis (EAE) animal model.
EAE animal model was induced by injection of MOG35-55 and monitored daily for clinical symptoms, and the treatment group was given Vesatolimod at the onset of illness. The therapeutic effects of Vesatolimod on EAE inflammation, demyelination, CD107b cells and T cells infiltration, and microglia activation was evaluated. Autophagy within the spinal cords of EAE mice was also preliminarily assessed.
Treatment with Vesatolimod significantly alleviated clinical symptoms of EAE from day 18 post-immunization and decreased the expression levels of inflammatory cytokines, particularly Eotaxin and IL-12 (P40), in peripheral blood. It also inhibited demyelination in spinal cords. Moreover, VES treatment reduced activation of microglia, infiltration of CD3 + T cells and CD107b + cells, as well as inhibited the autophagy-related proteins expression in the spinal cords of EAE mice.
Our results indicate that Vesatolimod exhibits protective effects on EAE mice and is promising for treatment of MS.
多发性硬化症是一种慢性脱髓鞘自身免疫性疾病，伴有炎症和轴突及神经元的丢失。 Toll 样受体在固有免疫系统和炎症中发挥着关键作用。然而，目前关于 Toll 样受体 7 信号通路在多发性硬化症中具体作用的研究较少。为了探索潜在的作用机制，开发新的治疗靶点，我们使用了安全且耐受性良好的 Toll 样受体 7 激动剂 Vesatolimod，评估其在实验性自身免疫性脑脊髓炎（EAE）动物模型中的可能作用。
通过注射 MOG35-55 诱导 EAE 动物模型，并每天监测临床症状，在发病时给予 Vesatolimod 治疗。评估 Vesatolimod 对 EAE 炎症、脱髓鞘、CD107b 细胞和 T 细胞浸润以及小胶质细胞激活的治疗作用。还初步评估了 EAE 小鼠脊髓内的自噬情况。
Vesatolimod 治疗可显著缓解免疫后第 18 天的 EAE 临床症状，并降低外周血中炎症细胞因子（特别是嗜酸性粒细胞趋化因子和 IL-12（P40））的表达水平。它还抑制脊髓中的脱髓鞘。此外，VES 治疗减少了 EAE 小鼠脊髓中小胶质细胞的激活、CD3+T 细胞和 CD107b+细胞的浸润，并抑制了自噬相关蛋白的表达。
我们的结果表明，Vesatolimod 对 EAE 小鼠具有保护作用，有望用于治疗多发性硬化症。
