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

ABSTRACT: In the present study, we analyzed single-cell multi-omics data from psoriasis patients and healthy individuals and found that more fibroblast-macrophage communication was present in the dermis of psoriasis lesions, exacerbating psoriasis progression. A natural product library was used to screen for a small molecule compound, celastrol, that could interfere with fibroblast-macrophage communication. It was demonstrated that celastrol targeted low-denisity lipoprotein receptor-related protein 1 (LRP1) to inhibit fibroblast secretion of CCL2 and inhibited psoriasis progression by reducing its recruitment to macrophages, thereby blocking communication between the two cells. Moreover, conditional knockdown of LRP1 by fibroblasts significantly improved psoriasis in mice, suggesting that LRP1 may be an important target for the treatment of psoriasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230842 | GEO | 2024/03/31

REPOSITORIES: GEO

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

Project description:Purpose: This study aimed to explore the mechanism of Celastrol in improving psoriasis through single-cell transcriptomics Methods: Supplementation with intragastric administration of celastrol in C57BL/6 mice to observe its effect on IMQ-induced psoriasis. Single-cell RNA sequencing were performed to explore the role of celastrol for IMQ-induced psoriasis. Results: A natural product library was used to screen for a small molecule compound, celastrol, that could interfere with fibroblast-macrophage communication. It was demonstrated that celastrol targeted low-denisity lipoprotein receptor-related protein 1 (LRP1) to inhibit fibroblast secretion of CCL2 and inhibited psoriasis progression by reducing its recruitment to macrophages, thereby blocking communication between the two cells Conclusion: We report that celastrol targeted low-denisity lipoprotein receptor-related protein 1 (LRP1) to inhibit fibroblast secretion of CCL2 and inhibited psoriasis progression by reducing its recruitment to macrophages. The use of celastrol maybe a noveltherapeuticoption for psoriasis.

2024-04-20 | GSE231728 | GEO

The Triptryium wilfordii derivative celastrol has anti-fibrotic effects in systemic sclerosis [Spatial Transcriptomics]

Project description:Objectives: Scleroderma (systemic sclerosis, SSc), as a prototypic inflammation-driven fibrotic disease, possesses connective tissue lesions populated with persistently activated myofibroblasts maintained by an mechanotranductive/pro-adhesive signaling loop. Drugs targeting this pathway are therefore of likely therapeutic benefit. The mechanosensitive transcriptional co-activator, yes activated protein-1 (YAP1), is activated in SSc fibroblasts. The terpenoid celastrol has recently been identified as a YAP1 inhibitor: however, if celastrol can alleviate SSc fibrosis is unknown. Methods: Human dermal fibroblasts from healthy individuals and patients with diffuse cutaneous SSc were treated with or without transforming growth factor b1 (TGFb1) in the presence or absence of celastrol. C57BL6J mice were subjected to the inflammatory-driven bleomycin-induced model of skin SSc, in the presence or absence of celastrol. RNA expression was assessed using RNAseq, real-time polymerase chain reaction and spatial transcriptomic analyses. Protein expression was determined using Western blot and enzyme-linked immunosorbent assay. Fibrosis was monitored by hematoxylin and eosin and trichrome staining, and indirect immunofluorescence analysis. Results: In dermal fibroblasts, celastrol impaired the ability of TGFβ1 to induce an SSc-like pattern of gene expression, including the induction of cellular communication network factor 2 (CCN2), collagen I and TGFβ1 protein. Celastrol alleviated the persistent fibrotic phenotype of dermal fibroblasts cultured from lesions of SSc patients. In the bleomycin-induced model of SSc dermatopathology, celastrol inhibited fibrosis and blocked nuclear localization of YAP in myofibroblasts. Conclusion: Our data are consistent with the hypothesis that compounds, such as celastrol, that antagonize the YAP pathway may be potential treatments for SSc skin fibrosis.

2023-11-01 | GSE226760 | GEO

The protective effect of celastrol in ANIT-induced cholestasis

Project description:Purpose: The goals of this study was to (1) evaluate the protective effect of celastrol on alpha-naphthylisothiocyanate (ANIT)-induced cholestasis and (2) which genes were recovered by celastrol. Methods:To investigate the protective effect of celastrol on ANIT-induced cholestasis, the WT mice were randomly assigned into two groups, respectively (n=3): (1) ANIT; (2) ANIT+Celastrol. ANIT+Celastrol group was orally treated with celastrol (10 mg/kg dissolved in 1% DMSO + 2% Tween 80 + 97% water) for 5 consecutive days. After celastrol was treated for 3 days, ANIT and ANIT+Celastrol groups were given a single oral dose of ANIT. All mice were killed 48 h after ANIT administration. Liver samples were harvested and frozen at -80 °C before analysis. Results: A total of 978 DEGs were identified. Large numbers of these DEGs were related to activation of SIRT1, which included increased FXR signaling and inhibition of PPARγ, nuclear factor-kappa B (NF-κB), and P53 signaling. Conclusions: Celastrol could protect ANIT-induced cholestasis by recovering disrupted Sirt1 level.

2018-02-09 | GSE110391 | GEO

Transcription profiling of human LNCaP cells treated with celastrol or vehicle for 6h

Project description:Celastrol is a natural product that affects LNCaP gene expression by 6h; We used microarrays to detail the global programme of gene expression affected by celastrol treatment at 6h Experiment Overall Design: LNCaP cells were grown to 50% confluency and treated with celastrol for 6h prior to direct Trizol lysis and RNA isolation

2008-11-07 | E-GEOD-5505 | biostudies-arrayexpress

The Triptryium wilfordii derivative celastrol has anti-fibrotic effects in systemic sclerosis [In vivo bulk RNA-seq]

2023-11-01 | GSE226375 | GEO

The Triptryium wilfordii derivative celastrol has anti-fibrotic effects in systemic sclerosis [in vitro bulk RNA-seq]

2023-11-01 | GSE226374 | GEO

Celastrol treatment on mouse embryonic fibroblasts (MEFs)

Project description:Celastrol has been shown to sensitize leptin receptor signaling and reduce ER stress. Current microarray data provide the gene expression profile in mouse embryonic fibroblasts (MEFs) after Celastrol treatment compared with control.

2016-07-08 | GSE84154 | GEO

PAI-1 derived cancer-associated fibroblasts in the esophageal squamous cell carcinoma promotes the migration and invasion of cancer cells and macrophages by interaction with LRP1

Project description:Cancer-associated fibroblasts (CAFs) are known to be involved in the progression of various cancers. However, the roles of CAFs in the esophageal squamous cell carcinoma (ESCC) microenvironment remain unclear. We previously co-cultured human bone marrow-derived mesenchymal stem cells (MSCs) with ESCC cells and confirmed the induction of fibroblast activation protein (FAP) in MSCs, which we defined as CAF-like cells. To investigate the roles of CAFs, we performed cDNA microarray analysis between MSCs and CAF-like cells and found that SERPINE1 was highly expressed in CAF-like cells when compared to MSCs. Plasminogen activator inhibitor-1 (PAI-1), encoded by SERPINE1, is generally accepted to play tumor promoting roles and act as a poor prognostic indicator in several cancers. PAI-1 derived from CAF-like cells promoted the cell migration and invasion of ESCC cells by activating Akt and Erk1/2 signaling pathways via low-density lipoprotein receptor related protein 1 (LRP1), the receptor of PAI-1. The higher expression levels of PAI-1 and LRP1 were correlated with the poor prognosis in ESCC patients. These results suggest that PAI-1/LRP1 axis contributes to the progression of ESCC.

2020-07-01 | GSE143138 | GEO

Hypothalamus of lean mice treated with celastrol or DMSO

Project description:Given that celastrol?s leptin-sensitizing effect requires high levels of circulating leptin, but lean mice have low levels of circulating leptin so that celastrol has no effect on lean mice. Analysis celastrol-induced hypothalamic gene expression profile change in lean mice will also be serving as negative control for DIO mice analysis.

2018-12-27 | GSE124356 | GEO

Simultaneous activation of heat shock and oxidative stress pathways by celastrol

Project description:Stress response pathways allow cells to rapidly sense and respond to deleterious environmental changes, including those caused by pathophysiological disease states. A previous screen for small molecules capable of activating the human heat shock response identified the triterpenoid celastrol as a potent activator of the heat shock transcription factor HSF1. We show here that celastrol likewise activates the homologous Hsf1 of Saccharomyces cerevisiae. Celastrol induced Hsf1 hyperphosphorylation and concurrently activated a synthetic transcriptional reporter as well as endogenous inducible Hsp70 proteins at the same effective concentration seen in mammalian cells. Moreover, celastrol treatment conferred significant resistance to subsequent lethal heat shock. Transcriptional profiling experiments revealed that in addition to Hsf1, celastrol treatment induced the Yap1-dependent oxidant defense regulon. Oxidative stress-responsive genes were likewise induced in mammalian cells, demonstrating that celastrol simultaneously activates two major cellular stress-mediating pathways. As the induction of cellular stress pathways has implications in the treatment of a variety of human diseases including neurodegenerative diosorders, cardiovascular disease and cancer, celastrol thus represents an attractive therapeutic compound. Keywords: single-dose, single time-point gene induction by natural small molecule celastrol compared to heat shock in wild type (BY4741) Saccahromyces cerevisiae

2006-08-26 | GSE5608 | GEO

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