Celastrol inhibits store operated calcium entry and suppresses psoriasis

Frontiers in Pharmacology

Pharmacology

Yilan Chen¹  Lijuan Zhou¹  Xiaoman Yuan¹  Yonggong Zhai¹  Youjun Wang²  Yandong Zhou³  Donald L. Gill³  Bin Tang⁴  Chuanjian Lu⁴  Jingwen Deng⁴  Lin Han⁴ 

[1] Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing, China;Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing, China;Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China;Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, United States;State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China;Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China;

关键词: psoriasis;    celastrol;    SOCE;    STIM1;    Orai1;    CRAC channel;    calcium;   

DOI  :  10.3389/fphar.2023.1111798

 received in 2022-11-30, accepted in 2023-01-20,  发布年份 2023

来源: Frontiers

【 摘 要 】

Introduction: Psoriasis is an inflammatory autoimmune skin disease that is hard to cure and prone to relapse. Currently available global immunosuppressive agents for psoriasis may cause severe side effects, thus it is crucial to identify new therapeutic reagents and druggable signaling pathways for psoriasis.Methods: To check the effects of SOCE inhibitors on psoriasis, we used animal models, biochemical approaches, together with various imaging techniques, including calcium, confocal and FRET imaging.Results and discussion: Store operated calcium (Ca2+) entry (SOCE), mediated by STIM1 and Orai1, is crucial for the function of keratinocytes and immune cells, the two major players in psoriasis. Here we showed that a natural compound celastrol is a novel SOCE inhibitor, and it ameliorated the skin lesion and reduced PASI scores in imiquimod-induced psoriasis-like mice. Celastrol dose- and time-dependently inhibited SOCE in HEK cells and HaCaT cells, a keratinocyte cell line. Mechanistically, celastrol inhibited SOCE via its actions both on STIM1 and Orai1. It inhibited Ca2+ entry through constitutively-active Orai1 mutants independent of STIM1. Rather than blocking the conformational switch and oligomerization of STIM1 during SOCE activation, celastrol diminished the transition from oligomerized STIM1 into aggregates, thus locking STIM1 in a partially active state. As a result, it abolished the functional coupling between STIM1 and Orai1, diminishing SOCE signals. Overall, our findings identified a new SOCE inhibitor celastrol that suppresses psoriasis, suggesting that SOCE pathway may serve as a new druggable target for treating psoriasis.

【 授权许可】

Unknown   
Copyright © 2023 Yuan, Tang, Chen, Zhou, Deng, Han, Zhai, Zhou, Gill, Lu and Wang.