PDF(Pubmed)
Abstract：
Cysteinyl leukotriene receptor 1 (CYSLTR1) is observed to increase in psoriatic skin lesions. Montelukast, a CYSLTR1 antagonist, effectively treats inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis, and atopic dermatitis. Thus, blocking CYSLTR1 may be a promising strategy for psoriasis immunotherapy. We prepared a montelukast sodium cream and solution and investigated their effects on psoriasis-like skin lesions induced by imiquimod (IMQ). After the treatment, serum, skin, and spleen samples were collected for evaluation. We treated human T helper (Th) 17 cells with montelukast in vitro to study its effect on Th17 differentiation and nuclear factor kappa-B (NF-κB) signaling. We also created a keratinocyte proliferation model induced by M5 cytokines and assessed the influence of montelukast on key psoriasis-related genes. We induced psoriasis in CYSLTR1 knockout (KO) mice using IMQ to explore the role of CYSLTR1 in psoriasis development. Montelukast sodium cream and solution effectively reduced the psoriasis area and severity index (PASI) and alleviated disease symptoms in IMQ-induced mice. Furthermore, reduced infiltration of inflammatory cells (Th1, Th17, and T follicular helper [Tfh] cells), decreased mRNA expression of cytokines in the skin (interleukin [IL]-17/F and IL-23), and lower serum concentrations of various cytokines (IL-2, IL-6, IL-13, and IL-17A/F) were observed. Montelukast cream and solution also decreased spleen size and the proportion of Th17 and Tfh cells, and significantly inhibited NF-κB signaling-related genes after application. Moreover, montelukast inhibited Th17 cell differentiation and suppressed NF-κB signaling in vitro. CYSLTR1 KO mice induced with IMQ showed improvement in PASI scores, serum IL-17A/F levels, and lower Th1 and Th17 cells in the spleen and skin compared to wild-type mice. Montelukast also suppressed the proliferation and inflammatory response of keratinocytes by regulating NF-κB signaling. Collectively, our results strongly indicate that inhibition of CYSLTR1 signaling to target the Th17 response holds significant promise as a therapeutic approach to manage psoriasis.
摘要：
在银屑病皮肤损伤中观察到半胱氨酰白三烯受体1(CYSLTR1)增加。孟鲁司特,CYSLTR1拮抗剂，有效治疗炎症性疾病，比如类风湿性关节炎，多发性硬化症,和特应性皮炎。因此，阻断CYSLTR1可能是银屑病免疫治疗的一个有前景的策略.我们制备了孟鲁司特钠乳膏和溶液，并研究了它们对咪喹莫特（IMQ）引起的牛皮癣样皮肤病变的影响。治疗后,血清,皮肤,收集脾脏样品进行评价。我们用孟鲁司特体外处理人T辅助（Th）17细胞，以研究其对Th17分化和核因子κB（NF-κB）信号传导的影响。我们还创建了M5细胞因子诱导的角质形成细胞增殖模型，并评估了孟鲁司特对关键银屑病相关基因的影响。我们使用IMQ在CYSLTR1敲除（KO）小鼠中诱导银屑病，以探讨CYSLTR1在银屑病发展中的作用。孟鲁司特钠乳膏和溶液可有效降低IMQ诱导小鼠的银屑病面积和严重程度指数（PASI），减轻疾病症状。此外，减少炎症细胞（Th1，Th17和T滤泡辅助[Tfh]细胞）的浸润，降低细胞因子在皮肤中的mRNA表达（白细胞介素[IL]-17/F和IL-23），观察到各种细胞因子(IL-2、IL-6、IL-13和IL-17A/F)的血清浓度较低。孟鲁司特乳膏和溶液也降低了脾脏大小和Th17和Tfh细胞的比例，应用后显著抑制NF-κB信号相关基因。此外，孟鲁司特体外抑制Th17细胞分化并抑制NF-κB信号传导。用IMQ诱导的CYSLTR1KO小鼠显示PASI评分改善，血清IL-17A/F水平，与野生型小鼠相比，脾脏和皮肤中的Th1和Th17细胞更低。孟鲁司特还通过调节NF-κB信号传导抑制角质形成细胞的增殖和炎症反应。总的来说，我们的结果强烈表明,抑制CYSLTR1信号传导以靶向Th17应答作为治疗银屑病的治疗方法具有重要前景.
