A bleomycin induced murine model of scleroderma in GSDMD-/- versus wild type
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ABSTRACT:
PROVIDER: PRJNA806648 | ENA |
REPOSITORIES: ENA
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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
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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.
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Project description:RNA-Seq analysis of skin from bleomycin induced scleroderma murine models treated with EHP-101
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Project description:Several lines of evidence have shown that the endocannabinoid system (ECS) may play a role in the pathophysiology of systemic sclerosis (SSc). Thereby, structurally different dual PPARγ/CB2 agonists such as VCE-004.8 and Ajulemic acid (AjA) have been shown to alleviate skin fibrosis and inflammation in experimental models of SSc. Since both compounds are currently being tested in humans, we were interested to identify similarities and differences in a murine model of SSc. One method available to assess this is the pharmacotranscriptomic signature of the individual compounds. To analyze the pharmacotranscriptomic signature, we used RNA-Seq to analyze the skin gene expression changes from bleomycin-induced fibrosis in mice treated orally with either AjA or EHP-101, a lipidic formulation of VCE-004.8. While both compounds prevented the upregulation of a common group of genes involved in the inflammatory and fibrotic components of the disease and the pharmacotranscriptomic signatures were similar for both compounds in some pathways, we found key differences between the compounds in several functional groups, including genes related the hypoxia, interferon-α and interferon-γ response. Additionally, we found 28 specific genes with translation potential by comparing our results with a list of intrinsic human scleroderma genes. Inmunohistochemical analysis revealed that both EHP-101 and AjA prevented bleomycin-induced skin fibrosis, collagen accumulation, and TNC and VCAM expression. However, only EHP-101 normalized the reduced expression of vascular CD31, CD34 and Von Willebrand factor markers, which parallels skin fibrosis, while AjA did not affect these markers. Finally, clear differences were also found in the plasmatic biomarker analysis, in which we found that EHP-101, but not AjA, enhanced the expression of some factors related to angiogenesis and vasculogenesis. Altogether the results indicate that dual PPARγ/CB2 agonists qualify as a novel therapeutic approach for the treatment of SSc and other fibrotic diseases as well, and that EHP-101 has unique mechanisms of action related to the pathophysiology of SSc which could be beneficial in treatment of this complex disease with no current therapeutic options.
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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.
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