Design of a gene signature to analyze the proinflammatory and the profibrotic polarization of murine fibroblasts and validation in an experimental murine model of scleroderma.
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PROVIDER: PRJNA790621 | ENA |
REPOSITORIES: ENA
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Project description:Scleroderma is an autoimmune connective tissue disease characterized by immune dysregulation, vasculopathy and fibrosis. We have previously demonstrated that low Fli1 expression in scleroderma fibroblasts and endothelial cells plays an important role in SSc pathogenesis. Cells of myeloid and lymphoid origin also express Fli1 and are dysregulated in patients with SSc, playing key roles in disease pathogenesis However, a role for immune Fli1 in SSc has not yet been described. Our aim was to elucidate whether Fli1 contributes to the immune dysregulation seen in scleroderma. Comparison of the expression of Fli1 in monocytes, B- and T-cell fractions of PBMCs isolated from scleroderma patients and healthy controls, showed an increase in Fli1 levels in monocytes. We used siRNA transfected human myeloid cells and mouse peritoneal macrophages obtained from Fli1flox/floxLysMCre+/+ mice, and found that markers of alternative macrophage activation were increased with Fli1 deletion. Coculture of Fli1-deficient myeloid cells and primary human or mouse fibroblasts resulted in a potent induction of collagen type I, independent of TGFβ upregulation. We next analyzed global gene expression profile in response to Fli1 downregulation, to gain further insight into the molecular mechanisms of this process and to identify differentially expressed genes in myeloid cells. Of relevance to SSc, the top most upregulated pathways were hallmark IFN-ɣ and IFN-α response. Additionally, several genes previously linked to SSc pathogenesis and fibrosis in general were also induced, including MCP-1, MCP-3, MMP12, and CXCL10. ANKRD1, a profibrotic transcription co-regulator was the top upregulated gene in our array. Our results show that Fli1-deficient myeloid cells share key features with cells from SSc patients, with higher expression of profibrotic markers and activation of interferon responsive genes, thus suggesting that low Fli1 may contribute to SSc pathogenesis.
2020-06-09 | GSE144625 | GEO
Project description:We provide an original multi-stage approach identifying a gene signature to assess the fibroblast polarization. Prototypic polarizations (inflammatory/fibrotic) were induced by seeded mouse embryonic fibroblasts (MEFs) with TNFα or TGFß1, respectively. The transcriptomic and proteomic profiles were obtained by RNA microarray and LC/MS-MS. Gene Ontology and pathways analysis were performed among the differentially expressed genes (DEGs) and proteins (DEPs). Balb/c mice underwent daily intradermal injections of HOCl (or PBS) as an experimental murine model of inflammation-mediated fibrosis in a time-dependent manner. As results, 1,456 and 2,215 DEGs, and 289 and 233 DEPs were respectively found in MEFs in response to TNFα or TGFß1, respectively. Among the most significant pathways, we combined 26 representative genes to encompass the proinflammatory and profibrotic polarizations of fibroblasts. Based on principal component analysis, this signature deciphered baseline state, proinflammatory polarization, and profibrotic polarization as accurately as did RNA microarray and LC/MS-MS. Then, we assessed the gene signature on dermal fibroblasts isolated from the experimental murine model. We observed a proinflammatory polarization at day 7, and a mixture of a proinflammatory and profibrotic polarizations at day 42 in line with histological findings. Our approach provides a small-size and convenient gene signature to assess murine fibroblast polarization.
2022-07-12 | PXD034078 | Pride
Project description:Fli1 downregulation in scleroderma myeloid cells has profibrotic and proinflammatory effects
| PRJNA604229 | ENA
Project description:Effect of TGFb1, TNFa, IL6-IL6R, IL1b on gene expression in Mouse Embryonnic Fibrobroblasts (3T3) using RNA microarrays.
2022-07-20 | GSE191223 | GEO
Project description:A murine systemic bleomycin model of scleroderma
| PRJNA549300 | ENA
Project description:Scleroderma (SSc) is an autoimmune connective tissue disease characterized by immune dysregulation, vasculopathy, and fibrosis. We have previously demonstrated that low Fli1 expression in SSc fibroblasts and endothelial cells plays an important role in SSc pathogenesis. Cells of myeloid and lymphoid origin also express Fli1 and are dysregulated in patients with SSc, playing key roles in disease pathogenesis. However, the role for immune Fli1 in SSc is not yet clear. Our aim was to elucidate whether Fli1 contributes to the immune dysregulation seen in SSc. Comparison of the expression of Fli1 in monocytes, B- and T-cell fractions of PBMCs isolated from SSc patients and healthy controls (HC), showed an increase in Fli1 levels in monocytes. We used siRNA transfected human myeloid cells and mouse peritoneal macrophages obtained from Fli1 flox/flox LysMCre+/+ mice, and found that markers of alternative macrophage activation were increased with Fli1 deletion. Coculture of Fli1-deficient myeloid cells and primary human or mouse fibroblasts resulted in a potent induction of collagen type I, independent of TGFβ upregulation. We next analyzed global gene expression profile in response to Fli1 downregulation, to gain further insight into the molecular mechanisms of this process and to identify differentially expressed genes in myeloid cells. Of relevance to SSc, the top most upregulated pathways were hallmark IFN-γ and IFN-α response. Additionally, several genes previously linked to SSc pathogenesis and fibrosis in general were also induced, including CCL2, CCL7, MMP12, and CXCL10. ANKRD1, a profibrotic transcription co-regulator was the top upregulated gene in our array. Our results show that Fli1-deficient myeloid cells share key features with cells from SSc patients, with higher expression of profibrotic markers and activation of interferon responsive genes, thus suggesting that dysregulation of Fli1 in myeloid cells may contribute to SSc pathogenesis.
| S-EPMC7248379 | biostudies-literature
Project description:Scleroderma is a lethal and currently irreversible autoimmune disease characterized by widespread tissue fibrosis and vasculopathy. Using cross-species comparative gene expression profiling we show that murine sclerodematous graft-versus-host disease (sclGVHD) approximates an “inflammatory” subset of human scleroderma and that both diseases demonstrate activation of the IL13 cytokine pathway. We report that both host myeloid cells expressing type I and II activated macrophage markers and graft T-cells produce IL13 and that host mice deficient in either IL13 or IL4Ra, an IL13 signal transducer, are protected from disease. This signaling pathway converges on a single gene, CCL2, which is coordinately upregulated in sclGVHD, in the human inflammatory scleroderma subset and in IL13 treated human dermal fibroblasts. Accordingly, treatment with antibodies to CCL2, and its murine homolog CCL12, prevent sclGVHD. Lastly, we provide evidence that IL13 pathway activation in early scleroderma patients correlates with modified Rodnan skin scores (mRSS). These data indicate that an inflammatory subset of scleroderma is driven by IL13 and may benefit from IL13 or CCL2 blockade.
2011-06-30 | GSE24409 | GEO
Project description:Scleroderma is a lethal and currently irreversible autoimmune disease characterized by widespread tissue fibrosis and vasculopathy. Using cross-species comparative gene expression profiling we show that murine sclerodematous graft-versus-host disease (sclGVHD) approximates an “inflammatory” subset of human scleroderma and that both diseases demonstrate activation of the IL13 cytokine pathway. We report that both host myeloid cells expressing type I and II activated macrophage markers and graft T-cells produce IL13 and that host mice deficient in either IL13 or IL4Ra, an IL13 signal transducer, are protected from disease. This signaling pathway converges on a single gene, CCL2, which is coordinately upregulated in sclGVHD, in the human inflammatory scleroderma subset and in IL13 treated human dermal fibroblasts. Accordingly, treatment with antibodies to CCL2, and its murine homolog CCL12, prevent sclGVHD. Lastly, we provide evidence that IL13 pathway activation in early scleroderma patients correlates with modified Rodnan skin scores (mRSS). These data indicate that an inflammatory subset of scleroderma is driven by IL13 and may benefit from IL13 or CCL2 blockade.
2011-06-30 | GSE24403 | GEO
Project description:Scleroderma is a lethal and currently irreversible autoimmune disease characterized by widespread tissue fibrosis and vasculopathy. Using cross-species comparative gene expression profiling we show that murine sclerodematous graft-versus-host disease (sclGVHD) approximates an “inflammatory” subset of human scleroderma and that both diseases demonstrate activation of the IL13 cytokine pathway. We report that both host myeloid cells expressing type I and II activated macrophage markers and graft T-cells produce IL13 and that host mice deficient in either IL13 or IL4Rα, an IL13 signal transducer, are protected from disease. This signaling pathway converges on a single gene, CCL2, which is coordinately upregulated in sclGVHD, in the human inflammatory scleroderma subset and in IL13 treated human dermal fibroblasts. Accordingly, treatment with antibodies to CCL2, and its murine homolog CCL12, prevent sclGVHD. Lastly, we provide evidence that IL13 pathway activation in early scleroderma patients correlates with modified Rodnan skin scores (mRSS). These data indicate that an inflammatory subset of scleroderma is driven by IL13 and may benefit from IL13 or CCL2 blockade.
2011-06-30 | GSE17914 | GEO
Project description:Scleroderma is a lethal and currently irreversible autoimmune disease characterized by widespread tissue fibrosis and vasculopathy. Using cross-species comparative gene expression profiling we show that murine sclerodematous graft-versus-host disease (sclGVHD) approximates an “inflammatory” subset of human scleroderma and that both diseases demonstrate activation of the IL13 cytokine pathway. We report that both host myeloid cells expressing type I and II activated macrophage markers and graft T-cells produce IL13 and that host mice deficient in either IL13 or IL4Ra, an IL13 signal transducer, are protected from disease. This signaling pathway converges on a single gene, CCL2, which is coordinately upregulated in sclGVHD, in the human inflammatory scleroderma subset and in IL13 treated human dermal fibroblasts. Accordingly, treatment with antibodies to CCL2, and its murine homolog CCL12, prevent sclGVHD. Lastly, we provide evidence that IL13 pathway activation in early scleroderma patients correlates with modified Rodnan skin scores (mRSS). These data indicate that an inflammatory subset of scleroderma is driven by IL13 and may benefit from IL13 or CCL2 blockade. sample vs reference. Total RNA isolated from a time course of primary adult dermal fibroblasts treated with 50nM recombinant IL4 over 24 hours
2011-06-30 | E-GEOD-24409 | biostudies-arrayexpress