Oral administration of a novel RORγt antagonist attenuates psoriasis-like skin lesion of two independent mouse models through neutralization of IL-17. Issue 1 (January 2017)

• Record Type: Journal Article
• Authors: Takaishi, Mikiro; Ishizaki, Masayuki; Suzuki, Keisuke; Isobe, Takashi; Shimozato, Takaichi; Sano, Shigetoshi
• Is Part Of: Journal of dermatological science. Volume 85:Issue 1(2017:Jan.)
• Page Start: 12
• Page End: 19
• Publication Date: 2017-01
• Subjects: Psoriasis -- RORγt -- Antagonist -- Mouse model -- Th17; Dermatology -- Periodicals; Skin Diseases -- Periodicals; Dermatologie -- Périodiques; 616.5005
• DOI: 10.1016/j.jdermsci.2016.10.001
• Languages: English
• ISSNs: 0923-1811

Abstract

Highlights: We have developed a novel RORγt antagonist, A213. A213 specifically binds to RORγt and inhibits murine Th17 differentiation in vitro . Oral administration of A213 attenuates psoriasis-like inflammation in mouse models. Abstract: Background: Targeting the IL-17 pathway represents a highly effective strategy for the treatment of psoriasis, using antibodies against IL-17A and IL-17 receptor, suggesting that Th17 cells essentially contribute to development of psoriasis. Th17 differentiation depends on the key transcription factor, RORγt. Objective: To develop a novel RORγt antagonist which is effective on psoriasis via oral administration. Methods: A chemical library was screened using cell-based high-throughput methods, luciferase reporter assay, competitive binding assay, and T cell differentiation assay. To evaluate in vivo effects of a novel RORγt antagonist, A213, we orally administrated it to two independent mouse models of psoriasis; IL-23-injection model and K5.Stat3C transgenic mouse. Results: Oral administration of A213 resulted in attenuation of skin inflammation in the both mouse models. At the same time, increased levels of IL-17A expression were significantly reduced in the skin lesions and skin-draining lymph nodes. Conclusion: These results implicate a new therapeutic application of RORγt antagonist for the treatment of psoriasis.