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Int J Biol Sci 2024; 20(6):2168-2186. doi:10.7150/ijbs.92514 This issue Cite

Research Paper

CYSLTR1 antagonist inhibits Th17 cell differentiation by regulating the NF-κB signaling for the treatment of psoriasis

Junpeng Zhao^1,2,3,4*, Yi Chen^1,2,3,4*, Liming Li^1,2,3,4*, Huiqi Yin^1,2,3,4*, Shasha Song^1,2,3,4, Yongfang Wang^1,2,3,4, Xiwei Feng^1,2,3,4, Xinyu Fan^1,2,3,4, Changxing Gao^1,2,3,4, Lingyu Gao^1,2,3,4, Yijing Zhan^1,2,3,4, Ming Zhao^1,2,3,4, Xinyu Li^1,2,3,4✉, Qianjin Lu^1,2,3,4✉

1. Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
2. Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
3. Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China.
4. Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
^* Junpeng Zhao, Yi Chen, Liming Li, and Huiqi Yin contributed equally to this work.

✉ Corresponding authors: Dr Qianjin Lu, Institute of Dermatology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, 210042, China; qianlu5860cams.cn, Phone: +86-731-85295860; Xinyu Li, Institute of Dermatology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, 210042, xinyusli609com, Phone: +86-731-85295860. More

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.

Keywords: Montelukast, CYSLTR1, Psoriasis, Th17 cell, NF-κB signaling

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