Celastrol targets LRP1 to inhibit fibroblast-macrophage crosstalk and ameliorates psoriasis progression
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ABSTRACT:
PROVIDER: PRJNA967368 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24441100.fastq.gz | Fastqsanger.gz | |||
| SRR24441098.fastq.gz | Fastqsanger.gz | |||
| SRR24441099.fastq.gz | Fastqsanger.gz |
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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.
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Project description: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.
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Project description:Celastrol targets LRP1 to inhibit fibroblast-macrophage crosstalk and ameliorates psoriasis progression
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Project description:Idiopathic pulmonary fibrosis (IPF), a chronic interstitial fibrosing pneumonia of unknown cause, is characterized by an irreversible decrease in alveolar cells and an increase in fibroblasts. In our research, the numbers of AT2 cells and fibroblasts are abnormally regulated, but AT1 cells are significantly reduced in lung tissue sections from patients with IPF and mice. By analyzing the single-cell sequence from GEO database and experimental validation both in vivo and in vitro, it is found that the abnormally regulated AT2 cells secreting a large amount of MDK to activate the CTHRC1+ fibroblasts LRP1 receptor and inhibit the ferroptosis of fibroblasts. Further, by activating the LRP1 receptor in CTHRC1+ fibroblasts, the RNA-seq results reveal that the expression level of OTUB1 increased significantly. The ubiquitination experiment results showed that OTUB1, as a deubiquitinated molecule, can directly bind to the ferroptosis inhibitory protein SLC7A11, removing the ubiquitination modification of SLC7A11 and stabilizing its expression level to inhibit ferroptosis in fibroblasts. Meanwhile, this molecular pathway was verified in mice by dropping adenovirus through the airway, and the same experimental results as in vitro were verified. In conclusion, our study verified that IPF leads to abnormal regulation of AT2 secreting MDK, which activates LRP1 receptor and increases OTUB1 in fibroblasts. Deubiquitylation modification of OTUB1 stabilizes the expression level of SLC7A11, which results in a decrease in fibroblast ferroptosis, leading to an abnormal regulation of its programmed death, ultimately the deterioration of IPF.
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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.
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