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A20 governs fibrosis susceptibility in bleomycin-induced mouse scleroderma model

ABSTRACT: A20 governs fibrosis susceptibility in bleomycin-induced mouse scleroderma model

PROVIDER: PRJNA800403 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17736523.fastq.gz	Fastqsanger.gz
	SRR17736524.fastq.gz	Fastqsanger.gz
	SRR17736525.fastq.gz	Fastqsanger.gz
	SRR17736526.fastq.gz	Fastqsanger.gz
	SRR17736527.fastq.gz	Fastqsanger.gz

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A20 governs fibrosis susceptibility in bleomycin-induced mouse scleroderma model

Project description:In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding A20 are also associated with systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to fibrosis in SSc, and which cell types drive disease due to SSc-specific genetic alterations. We characterized the expression and function of A20, and its negative transcriptional regulator DREAM, in patient with SSc. We found that levels of A20 were significantly reduced in SSc skin and lung biopsies, while DREAM was elevated and showed anti-correlation with A20. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulated major pathological and genomic features of SSc, whereas DREAM-null mice showed elevated A20 expression and were protected from fibrosis. In fibroblasts, A20 mitigated ex vivo profibrotic responses. An anti-fibrotic small molecule targeting the adiponectin receptors stimulated A20 expression in vitro in wildtype but not A20-deficient fibroblasts, and in bleomycin-treated mice. Thus, A20 has a novel function in negative regulation of fibroblast responses, and together with DREAM, constitutes a critical regulatory network governing the fibrotic process in SSc, suggesting that A20 and DREAM represent novel druggable targets.

2022-02-01 | GSE194380 | GEO

A murine systemic bleomycin model of scleroderma

Project description:A murine systemic bleomycin model of scleroderma

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A bleomycin induced murine model of scleroderma in GSDMD-/- versus wild type

Project description:The NLRP3 inflammasome and IL-1β are essential for scleroderma pathogenesis. Nevertheless, the role of pyroptosis executor gasdermin D(GSDMD), which is a downstream molecule of NLRP3 and is required for IL-1β release in some situations, has not yet been well elucidated in scleroderma. The purpose of this study was to explore the differences in the degree of skin fibrosis between GSDMD-/- and wild type mice in a bleomycin-induced scleroderma model, and the molecular pathways that may be involved.Total RNA from skin biopsies from GSDMD-/- and wild type mice after subcutaneous injection of BLM to induce skin fibrosis was examined by nextGen RNA sequencing

2022-02-16 | GSE196637 | GEO

Alteration of m6A epitranscriptome profile in the bleomycin-treated mouse model of scleroderma

Project description:The exploration of m6A methylation in scleroderma remains in its infancy. We aimed to reveal the landscape of m6A methylated long noncoding RNAs (lncRNAs) and small RNAs in scleroderma.

2023-03-27 | GSE226331 | GEO

A murine systemic bleomycin model of scleroderma

Project description:A well-characterized mouse model of SSc involves daily subcutaneous injections of the antitumor antibiotic bleomycin (BLM), which leads to localized dermal fibrosis as well as pulmonary fibrosis. We have termed this the “Systemic Bleomycin Model” to distinguish it from the already-established Intratracheal (IT) model. We utilize this model, which mimics several key features of human SSc, to examine the pathological mechanisms underlying the development and progression of fibrosis in SSc.

2019-06-18 | GSE132869 | GEO

Transcriptome analysis of the scleroderma skin tissue treated with BMSC derived exosome in mouse

Project description:We aim to explore the transcriptome of the dermis of the bleomycin induced murine scleroderma model which were treated with PBS or bone marrow stem cell derived exosome.

2021-06-15 | GSE165117 | GEO

RNA-Seq analysis of skin from bleomycin induced scleroderma murine models treated with EHP-101

Project description:Systemic sclerosis (SSc) or scleroderma is a chronic multiorgan autoimmune disease of unknown etiology characterized by vascular, immunological and fibrotic abnormalities. Several lines of evidence have shown that the endocannabinoid system (ECS) may play a role in the pathophysiology of SSc. VCE-004.8, a CBD aminoquinone derivative, is a dual PPARγ/CB2 that alleviates bleomycin (BLM)-induced skin fibrosis. Herein we report that EHP-101, an oral lipidic formulation of VCE-004.8, prevents skin and lung fibrosis and collagen accumulation in BLM challenged mice. Immunohistochemistry analysis of the skin demonstrate that EHP-101 prevents macrophage infiltration, and the expression of Tenascin C (TNC), VCAM, and the α-smooth muscle actin (SMA). In addition, a reduced expression of vascular CD31, paralleling skin fibrosis, was also prevented by EHP-101. RNAseq analysis in skin biopsies showed a clear effect of EHP-101 in the inflammatory and epithelial-mesenchymal transition transcriptomic signatures. TGF-beta regulated genes such as matrix metalloproteinase-3 (Mmp3), cytochrome b-245 heavy chain (Cybb), lymphocyte antigen 6E (Ly6e), vascular cell adhesion molecule-1 (Vcam1) and the Integrin alpha-5 (Itga5) were induced in BLM mice and repressed by EHP-101 treatment. We also intersected differentially expressed genes in EHP-101-treated mice with dataset of human scleroderma intrinsic genes and found 53 overlapped genes, including the C-C motif chemokine 2 (Ccl2) and the interleukin 13 receptor subunit alpha 1 (IL-13Ra1) genes, which have been studied as biomarkers of SSc. Altogether the results indicate that this synthetic cannabinoid qualifies as a novel compound for the management and possible treatment of scleroderma and, potentially, other fibrotic diseases.

2018-10-02 | GSE115503 | GEO

A bleomycin induced murine model of scleroderma in GSDMD-/- versus wild type

Project description:A bleomycin induced murine model of scleroderma in GSDMD-/- versus wild type

| PRJNA806648 | ENA

RNA sequencing of CRISPR/Cas9-generated A20 DUB-inative and A20 knock-out U937 cells to elucidate the role of human A20 DUB-domain

Project description:Objectives: Genetic variations in TNFAIP3 (A20) de-ubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-κB but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis. Methods: CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A knock-in cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was adressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926. Results: Genetic disruption of A20 DUB domain in human and murine myeoloid cells did not give rise to enhanced NF-κB signaling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes. Conclusions: We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.

2019-07-10 | GSE116780 | GEO

Alteration of m6A epitranscriptome profile in the bleomycin-treated mouse model of scleroderma

Project description:Alteration of m6A epitranscriptome profile in the bleomycin-treated mouse model of scleroderma

| PRJNA939720 | ENA