National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China.
Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.
Immunology. 2021 Jun;163(2):185-200. doi: 10.1111/imm.13308. Epub 2021 Feb 28.
Montelukast is a leukotriene receptor antagonist that is known to prevent allergic rhinitis and asthma. Blocking the Cysteinyl leukotriene receptor (CysLTR1), one of the primary receptors of leukotrienes, has been demonstrated to be efficacious in ameliorating experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), through disrupting chemotaxis of infiltrating T cells. However, the role of CysLTR1 in the pathogenesis of MS is not well understood. Here, we show that MS patients had higher expression of CysLTR1 in the circulation and central nervous system (CNS). The majority of CD4 T cells expressed CysLTR1 in MS lesions. Among T-cell subsets, Th17 cells had the highest expression of CysLTR1, and blocking CysLTR1 signalling abrogated their development in vitro. Inhibition of CysLTR1 by montelukast suppressed EAE development in both a prophylactic and therapeutic manner and inhibited myelin loss in EAE mice. Similarly, the in vivo results showed that montelukast inhibited Th17 response in EAE mice and that Th17 cells treated with montelukast had reduced encephalitogenic in adoptive EAE. Our findings strongly suggest that targeting Th17 response by inhibiting CysLTR1 signalling could be a promising therapeutic strategy for the treatment of MS and CNS inflammatory diseases.
孟鲁司特是一种白三烯受体拮抗剂，已知可预防过敏性鼻炎和哮喘。阻断白三烯的主要受体之一半胱氨酰白三烯受体 1（CysLTR1），已被证明通过破坏浸润 T 细胞的趋化作用，在改善实验性自身免疫性脑脊髓炎（EAE），即多发性硬化症（MS）的动物模型中是有效的。然而，CysLTR1 在 MS 发病机制中的作用尚不清楚。在这里，我们表明 MS 患者在循环和中枢神经系统（CNS）中表达更高水平的 CysLTR1。在 MS 病变中，大多数 CD4 T 细胞表达 CysLTR1。在 T 细胞亚群中，Th17 细胞表达最高水平的 CysLTR1，阻断 CysLTR1 信号可在体外阻止其发育。孟鲁司特抑制 CysLTR1 可通过预防和治疗方式抑制 EAE 的发展，并抑制 EAE 小鼠的髓鞘丢失。同样，体内结果表明，孟鲁司特抑制 EAE 小鼠中的 Th17 反应，并且用孟鲁司特处理的 Th17 细胞在过继性 EAE 中具有降低的致脑炎能力。我们的研究结果强烈表明，通过抑制 CysLTR1 信号靶向 Th17 反应可能是治疗 MS 和中枢神经系统炎症性疾病的一种有前途的治疗策略。
