Circulating proinflammatory cytokines alter transcriptional activity within fibrotic tissue of Dupuytren’s disease patients
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE169477 | GEO | 2021/06/01
REPOSITORIES: GEO
Similar Datasets
Project description:Circulating proinflammatory cytokines alter transcriptional activity within fibrotic tissue of Dupuytren’s disease patients
| PRJNA716676 | ENA
Project description:Darier disease (DD) is a rare, inherited multi-organ disorder associated with mutations in the ATP2A2 gene. In DD patients, the skin is frequently affected, characterized by malodorous, inflamed skin and recurrent, severe infections. Therapeutic options are limited and inadequate for the long-term management of this chronic disease. Using immunoprofiling with NanoString technology, qPCR and immunohistochemistry, we demonstrate enhanced expression of Th-17-related genes and cytokines in six DD patients. We prove that targeting the IL-23/-17 axis in DD with monoclonal antibodies is an effective and safe therapy in DD patients, leading to significant clinical improvement. As DD is a chronic, relapsing disease, our findings provide new options for the long-term management of skin inflammation in patients with DD.
2023-09-25 | GSE235255 | GEO
Project description:Dupuytren’s disease (DD) is a common, progressive fibroproliferative disease affecting the palmar fascia of the hands, causing fingers to irreversibly flex towards the palm with significant loss of function. Surgical treatments are limited, therefore effective new therapies for DD are urgently required. To identify key cellular and molecular pathways driving DD we employed single-cell RNA sequencing (scRNA-seq), profiling the transcriptomes of 35,250 human single cells from DD, non-pathogenic fascia, and healthy dermis. We identify a DD-specific population of pathogenic PDPN+/FAP+ mesenchymal cells displaying elevated expression of fibrillar collagens and profibrogenic genes. In silico trajectory analysis reveals resident fibroblasts to be the source of this pathogenic population. To resolve the processes governing DD progression, genes differentially expressed during fibroblast differentiation were identified including upregulated TNFRSF12A and transcription factor SCX. Knockdown of SCX and blockade of TNFRSF12A inhibited proliferation and altered pro-fibrotic gene expression of cultured human FAP+ mesenchymal cells, demonstrating a functional role for these genes in DD. The power of scRNA-seq is utilised to identify the major pathogenic mesenchymal subpopulations driving DD and key molecular pathways regulating the DD-specific myofibroblast phenotype. Using this precision medicine approach, inhibition of TNFRSF12A has shown potential clinical utility in the treatment of Dupuytren’s disease.
2021-05-03 | GSE173252 | GEO
Project description:As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast – the primary effector of the fibroproliferative response. A central unanswered question is whether these myofibroblasts have acquired a distinct pathological phenotype - or whether they are normal myofibroblasts with a pathological phenotype that depends upon residing in a sea of pro-fibrotic cytokines and an abnormal extracellular matrix. Using a systems approach to study this question in a prototype fibrotic disease, Idiopathic Pulmonary Fibrosis (IPF); here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition (EMT). In accord with this, we found systems-level indications for TGF?b -driven EMT as one source of IPF myofibroblasts. Keywords: cell type comparison Comparison of lung myofibroblasts from patients with Idiopatic Pulmonary Fibrosis (IPF, 6 donors) to control (6 donors) in contractile and non-contractile matrices using both total and polyribosomal RNA
2008-11-20 | E-GEOD-11196 | biostudies-arrayexpress
Project description:Pathway expression analysis in systemic sclerosis revealed key mediators driving pathology within each of the intrinsic gene expression subsets. Genome-wide expression profiling in systemic sclerosis (SSc) has identified four 'intrinsic' subsets of disease (fibroproliferative, inflammatory, limited, and normal-like), each of which appear to be driven by distinct signaling pathways. Here we examine experimentally derived gene expression signatures for thirteen agonists to better understand the molecular mechanisms underlying each intrinsic subsets. Pathway-specific gene signatures were compared against skin biopsy microarray data consisting of 329 microarray hybridizations from 287 unique biopsies representing 111 patients. Hierarchical clustering recapitulated the four SSc 'intrinsic' gene expression subsets, along with an intermediate subset exhibiting both inflammatory and fibroproliferative gene expression signatures. The fibroproliferative subset is most strongly associated with the PDGF gene signature, while the inflammatory subset demonstrated strong activation of NF-kappaB, characterized by early induction of TH2 signals, which transitions to a more TH17-like immune response over time. The limited subset was associated with IFNalpha signaling, combined with strong downregulation of PDGF signaling. The inflammatory-proliferative subset shows downregulation of NF-kappaB-associated pathways in conjunction with increased PDGF signaling, suggestive of a transitional state linking the inflammatory and fibroproliferative subsets. IL-13 signaling was strongly associated with early disease, while TGFbeta signaling was associated with more severe disease. Together these data suggest a multi-step, progressive model of disease pathogenesis driven by distinct pathways. Targeting these pathways based upon a patient's underlying disease subset should improve therapeutic outcomes. In vitro treatment of human dermal fibroblasts was performed to identify pathway-specific gene signatures. These gene signatures were then compared against systemic sclerosis skin biopsy microarrays to determine the overall contribution of each pathway to disease. This study includes re-analysis of 247 skin biopsy samples from GSE9285, GSE32413, and GSE45485. Links to these Samples are provided below. The re-processed normalized data for these Samples are included in the supplementary file 'GSE56308_247_Skin_Biopsy_Reanalysis_Samples.txt'.
2015-04-01 | E-GEOD-56308 | biostudies-arrayexpress
Project description:Pathway expression analysis in systemic sclerosis revealed key mediators driving pathology within each of the intrinsic gene expression subsets. Genome-wide expression profiling in systemic sclerosis (SSc) has identified four 'intrinsic' subsets of disease (fibroproliferative, inflammatory, limited, and normal-like), each of which appear to be driven by distinct signaling pathways. Here we examine experimentally derived gene expression signatures for thirteen agonists to better understand the molecular mechanisms underlying each intrinsic subsets. Pathway-specific gene signatures were compared against skin biopsy microarray data consisting of 329 microarray hybridizations from 287 unique biopsies representing 111 patients. Hierarchical clustering recapitulated the four SSc 'intrinsic' gene expression subsets, along with an intermediate subset exhibiting both inflammatory and fibroproliferative gene expression signatures. The fibroproliferative subset is most strongly associated with the PDGF gene signature, while the inflammatory subset demonstrated strong activation of NF-kappaB, characterized by early induction of TH2 signals, which transitions to a more TH17-like immune response over time. The limited subset was associated with IFNalpha signaling, combined with strong downregulation of PDGF signaling. The inflammatory-proliferative subset shows downregulation of NF-kappaB-associated pathways in conjunction with increased PDGF signaling, suggestive of a transitional state linking the inflammatory and fibroproliferative subsets. IL-13 signaling was strongly associated with early disease, while TGFbeta signaling was associated with more severe disease. Together these data suggest a multi-step, progressive model of disease pathogenesis driven by distinct pathways. Targeting these pathways based upon a patient's underlying disease subset should improve therapeutic outcomes.
2015-04-01 | GSE56308 | GEO
Project description:Darier disease (DD) is a rare, inherited multi-organ disorder associated with mutations in the ATP2A2 gene. In DD patients, the skin is frequently affected, characterized by malodorous, inflamed skin and recurrent, severe infections. Therapeutic options are limited and inadequate for the long-term management of this chronic disease. Using immunoprofiling with NanoString technology we demonstrate enhanced expression of Th-17-related genes and cytokines in five DD patients. We prove that targeting the IL-23/-17 axis in DD with monoclonal antibodies is an effective and safe therapy in DD patients, leading also to significant clinical improvement.
2023-09-23 | GSE222043 | GEO
Project description:As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast – the primary effector of the fibroproliferative response. A central unanswered question is whether these myofibroblasts have acquired a distinct pathological phenotype - or whether they are normal myofibroblasts with a pathological phenotype that depends upon residing in a sea of pro-fibrotic cytokines and an abnormal extracellular matrix. Using a systems approach to study this question in a prototype fibrotic disease, Idiopathic Pulmonary Fibrosis (IPF); here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition (EMT). In accord with this, we found systems-level indications for TGF-beta -driven EMT as one source of IPF myofibroblasts. Keywords: cell type comparison
2008-11-21 | GSE11196 | GEO
Project description:Exposure to proinflammatory cytokines is believed to contribute to pancreatic β-cells during diabetes development. While some cytokine-mediated changes in islet gene expression are known, the heterogeneity of the response is not well-understood. Following 6 hour treatment with interleukin-1 beta (IL-1β) and interferon-gamma (IFN-γ) alone or together, mouse islets were subjected to single-cell RNA-sequencing (scRNA-seq). Inducible nitric oxide synthase (iNOS) mRNA (Nos2), antiviral genes, and immune-associated genes were induced in a subset of β-cells in response to both cytokines, while IL-1β alone activated only antiviral genes. Subsets of α- and δ-cells expressed Nos2 and exhibited similar gene expression changes as β-cells, including induction of antiviral genes and repression of identity genes. Finally, cytokine-responsiveness was inversely correlated with expression of genes encoding heat shock proteins. Our findings show that all endocrine cell types respond to cytokines, IL-1β induces the expression of protective genes in β-cells, and cellular stress gene expression is associated with an inhibition in cytokine signaling.
2021-04-15 | GSE156175 | GEO