Celastrol directly targets LRP1 to inhibit fibroblast-macrophage crosstalk and ameliorates psoriasis progression

• DOI: 10.1016/j.apsb.2024.12.041
• Publication Date: 2025-01-05T06:48:07Z
• Authors: Yuyu Zhu; Lixin Zhao; Wei Yan; Hongyue Ma; Wanjun Zhao; Jiao Qu; Wei Zheng; Chenyang Zhang; Haojie Du; Meng Yu; Ning Wan; Hui Ye; Yicheng Xie; Bowen Ke; Qiang Xu; Haiyan Sun; Yang Sun; Zijun Ouyang
• Keywords: Macrophage; LRP1; Psoriasis; Fibroblast; Therapeutics. Pharmacology; RM1-950; Celastrol; CCL2

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.