A20 governs fibrosis susceptibility in bleomycin-induced mouse scleroderma model
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ABSTRACT:
PROVIDER: PRJNA800403 | ENA |
REPOSITORIES: ENA
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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
Project description:A murine systemic bleomycin model of scleroderma
| PRJNA549300 | ENA
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
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
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
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
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
Project description:A bleomycin induced murine model of scleroderma in GSDMD-/- versus wild type
| PRJNA806648 | ENA
Project description:Pulmonary fibrosis is a disease characterized by inflammatory cell infiltration, scar formation, deposition of extracellular matrix, alveolar epithelial cell injury and hyperplasia. To determine if alterations in microRNA expression contribute to these phenotypes, microRNA expression profiling of the lungs from bleomycin treated C57Bl/6J mice, relative to that of untreated controls, was undertaken. Mice were treated at 8 weeks old with 100 Units/kg of bleomycin delivered subcutaneously with osmotic minipumps. At 42 days post treatment mice were euthanized and lung microRNA isolated. We identified 11 microRNA's to be significantly differentially expressed (FDR threshold of 0.01) in the lungs of bleomycin treated mice and confirmed these data with real time PCR measurements. These included bleomycin upregulated miR-34a, 335-5p, 207, 21, 301a, 146b, 199a-5p, and 449a and bleomycin downregulated miR-151-3p, 26a and 676. We have previously shown that 1558 genes are differentially expressed in the lungs of bleomycin treated mice. Of the 1412 targets of upregulated microRNAs, 142 were confirmed to be downregulated in the gene expression profile (GEP). Of the 583 targets of downregulated microRNAs, 53 were confirmed to be upregulated in the gene expression profile. Pathway analysis of the microRNA targets and GEP overlapping genes indicated that altered microRNA expression is associated with cellular development, cellular growth, cellular proliferation and changed tissue/cell morphology. Specific pathways include HGF signaling, Cholecystokinin/Gastrin-mediated signaling, Endothelin-1 signaling, RAR activation, Phospholipase C signaling and IGF1 signaling. We conclude that altered microRNA expression is a feature of pulmonary fibrosis which putatively influences components of the altered airway disease. Two condition study, C57Bl/6J mice treated with 100 Units/kg bleomycin and untreated controls. Biological replicated n =3 for each group. Left lung tissue.
2013-09-01 | E-GEOD-45789 | biostudies-arrayexpress
Project description:We assessed transcriptomic changes in fibroblasts isolated from skin biopsies from diffuse cutaneous scleroderma patients before and after BET inhibitor JQ1 treatment
2022-03-01 | GSE186961 | GEO