Celastrol directly targets LRP1 to inhibit fibroblast-macrophage crosstalk and ameliorates psoriasis progression.
10.1016/j.apsb.2024.12.041
- Author:
Yuyu ZHU
1
;
Lixin ZHAO
2
;
Wei YAN
3
;
Hongyue MA
1
;
Wanjun ZHAO
2
;
Jiao QU
2
;
Wei ZHENG
2
;
Chenyang ZHANG
2
;
Haojie DU
2
;
Meng YU
1
;
Ning WAN
4
;
Hui YE
4
;
Yicheng XIE
5
;
Bowen KE
6
;
Qiang XU
2
;
Haiyan SUN
7
;
Yang SUN
2
;
Zijun OUYANG
7
Author Information
1. Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
2. State Key Laboratory of Pharmaceutical Biotechnology and Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, School of Life Sciences, Nanjing University, Nanjing 210008, China.
3. Department of Dermatology and Venereology, West China Hospital, Sichuan University, Chengdu 610041, China.
4. Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
5. The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China.
6. Department of Anesthesiology, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China.
7. School of Food and Drug, Shenzhen Polytechnic University, Shenzhen 518055, China.
- Publication Type:Journal Article
- Keywords:
CCL2;
Celastrol;
Drug target;
Fibroblast;
LRP1;
Macrophage;
Psoriasis;
c-Jun
- From:
Acta Pharmaceutica Sinica B
2025;15(2):876-891
- CountryChina
- Language:English
-
Abstract:
Psoriasis is an incurable chronic inflammatory disease that requires new interventions. Here, we found that fibroblasts exacerbate psoriasis progression by promoting macrophage recruitment via CCL2 secretion by single-cell multi-omics analysis. The natural small molecule celastrol was screened to interfere with the secretion of CCL2 by fibroblasts and improve the psoriasis-like symptoms in both murine and cynomolgus monkey models. Mechanistically, celastrol directly bound to the low-density lipoprotein receptor-related protein 1 (LRP1) β-chain and abolished its binding to the transcription factor c-Jun in the nucleus, which in turn inhibited CCL2 production by skin fibroblasts, blocked fibroblast-macrophage crosstalk, and ameliorated psoriasis progression. Notably, fibroblast-specific LRP1 knockout mice exhibited a significant reduction in psoriasis like inflammation. Taken together, from clinical samples and combined with various mouse models, we revealed the pathogenesis of psoriasis from the perspective of fibroblast-macrophage crosstalk, and provided a foundation for LRP1 as a novel potential target for psoriasis treatment.
