Nuclear receptor subfamily 4A signaling as a key disease pathway of CD1c+ dendritic cell dysregulation in systemic sclerosis
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PROVIDER: PRJNA772941 | ENA |
REPOSITORIES: ENA
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Project description:Objectives: To identify key pathways, transcriptional regulators and epigenetic mechanisms underlying conventional dendritic cell (cDC) alteration in Systemic Sclerosis (SSc). Methods: Transcriptomic profiling was performed on CD1c+ cDCs isolated from peripheral blood samples obtained from 12 healthy donors and 48 SSc patients with all major disease subtypes. Differential expression analysis comparing the different SSc subtypes and healthy donors was performed to uncover genes dysregulated in SSc. To identify biologically relevant pathways, a gene co-expression network was built using the Weighted Gene Correlation Network Analysis. We validated the role of key transcriptional regulators using ChIP-sequencing and in vitro functional assays. Results: We identified 17 modules of co-expressed genes in cDCs that correlated with SSc subtypes and key clinical traits. A module of immune regulatory genes was markedly down regulated in patients with the diffuse SSc subtype suffering from severe fibrosis. Gene regulatory network analysis performed on the immune regulatory module predicted NR4A (nuclear receptor 4A) subfamily (NR4A1, NR4A2, NR4A3) genes as the master transcriptional mediators of inflammation. Indeed, ChIP-sequencing analysis of cDCs supported that these NR4A members target numerous differentially expressed genes in SSc cDCs. Inclusion of NR4A receptor agonists in culture-based experiments provided functional proof that dysregulation of NR4As affects cytokine production by cDCs and modulates T-cells activation. Conclusions: NR4A1, NR4A2 and NR4A3 are important regulators of immunosuppressive and fibrosis-associated pathways in SSc cDCs. Thus, the NR4A family represent novel potential targets to restore cDC homeostasis in SSc.
2023-03-22 | GSE186198 | GEO
Project description:Objectives: To identify key pathways, transcriptional regulators and epigenetic mechanisms underlying conventional dendritic cell (cDC) alteration in Systemic Sclerosis (SSc). Methods: Transcriptomic profiling was performed on CD1c+ cDCs isolated from peripheral blood samples obtained from 12 healthy donors and 48 SSc patients with all major disease subtypes. Differential expression analysis comparing the different SSc subtypes and healthy donors was performed to uncover genes dysregulated in SSc. To identify biologically relevant pathways, a gene co-expression network was built using the Weighted Gene Correlation Network Analysis. We validated the role of key transcriptional regulators using ChIP-sequencing and in vitro functional assays. Results: We identified 17 modules of co-expressed genes in cDCs that correlated with SSc subtypes and key clinical traits. A module of immune regulatory genes was markedly down regulated in patients with the diffuse SSc subtype suffering from severe fibrosis. Gene regulatory network analysis performed on the immune regulatory module predicted NR4A (nuclear receptor 4A) subfamily (NR4A1, NR4A2, NR4A3) genes as the master transcriptional mediators of inflammation. Indeed, ChIP-sequencing analysis of cDCs supported that these NR4A members target numerous differentially expressed genes in SSc cDCs. Inclusion of NR4A receptor agonists in culture-based experiments provided functional proof that dysregulation of NR4As affects cytokine production by cDCs and modulates T-cells activation. Conclusions: NR4A1, NR4A2 and NR4A3 are important regulators of immunosuppressive and fibrosis-associated pathways in SSc cDCs. Thus, the NR4A family represent novel potential targets to restore cDC homeostasis in SSc.
2023-03-22 | GSE186197 | GEO
Project description:Nuclear receptor subfamily 4A signaling as a key disease pathway of CD1c+ dendritic cell dysregulation in systemic sclerosis [ChIP-seq]
| PRJNA772944 | ENA
Project description:Nuclear receptor subfamily 4A signaling as a key disease pathway of CD1c+ dendritic cell dysregulation in systemic sclerosis [RNA-seq]
| PRJNA772943 | ENA
Project description:ObjectiveThis study was undertaken to identify key disease pathways driving conventional dendritic cell (cDC) alterations in systemic sclerosis (SSc).MethodsTranscriptomic profiling was performed on peripheral blood CD1c+ cDCs (cDC2s) isolated from 12 healthy donors and 48 patients with SSc, including all major disease subtypes. We performed differential expression analysis for the different SSc subtypes and healthy donors to uncover genes dysregulated in SSc. To identify biologically relevant pathways, we built a gene coexpression network using weighted gene correlation network analysis. We validated the role of key transcriptional regulators using chromatin immunoprecipitation (ChIP) sequencing and in vitro functional assays.ResultsWe identified 17 modules of coexpressed genes in cDCs that correlated with SSc subtypes and key clinical traits, including autoantibodies, skin score, and occurrence of interstitial lung disease. A module of immunoregulatory genes was markedly down-regulated in patients with the diffuse SSc subtype characterized by severe fibrosis. Transcriptional regulatory network analysis performed on this module predicted nuclear receptor 4A (NR4A) subfamily genes (NR4A1, NR4A2, NR4A3) as the key transcriptional regulators of inflammation. Indeed, ChIP-sequencing analysis indicated that these NR4A members target numerous differentially expressed genes in SSc cDC2s. Inclusion of NR4A receptor agonists in culture-based experiments provided functional proof that dysregulation of NR4As affects cytokine production by cDC2s and modulates downstream T cell activation.ConclusionNR4A1, NR4A2, and NR4A3 are important regulators of immunosuppressive and fibrosis-associated pathways in SSc cDCs. Thus, the NR4A family represents novel potential targets to restore cDC homeostasis in SSc.
| S-EPMC10108054 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-03-22 | GSE186199 | GEO
Project description:In this study gene expression of CD1c+ CD19- blood dendritic cells from healthy subjects were investigated. Keywords: expression profiling by array Blood DCs (CD1c+ CD19-) were isolated from venous heparinized blood of three apparently healthy human volunteers using the CD1c+ (BDCA-1) dendritic cell isolation kit from Miltenyi according to the manufacturer’s instructions. Purity over 90% (95.8±3%) was determined by FACS analysis. RNA was isolated and 1 µg was labeled using the Affymetrix One-Cycle Target Labeling Kit and the biotinylated cRNA used to perform Affymetrix U133 Plus 2.0 expression arrays.
2011-12-17 | E-GEOD-34515 | biostudies-arrayexpress
Project description:In comparison to murine dendritic cells (DCs), less is known about the function of human DCs in tissues. Here, we analyzed, using lung tissues from humans and humanized mice, the role of human CD1c+ and CD141+ DCs in determining the type of CD8+ T cell immunity to live-attenuated influenza virus (LAIV) vaccine. We found that both lung DC subsets acquired influenza antigens in vivo and expanded specific cytotoxic CD8+ T cells in vitro. However, lung-tissue-resident CD1c+ DCs but not CD141+ DCs were able to drive CD103 expression on CD8+ T cells and promote CD8+ T cell accumulation in lung epithelia in vitro and in vivo. CD1c+ DCs induction of CD103 expression was dependent on membrane-bound TGF-?1. Thus, CD1c+ and CD141+ DCs generate CD8+ T cells with different properties, and CD1c+ DCs specialize in the regulation of mucosal CD8+ T cells. Total RNA were isolated from purified human CD1c+ (BDCA1+) and CD141+ (BDCA3+) mDCs sorted from different tissues, including human blood, spleen and lungs of humanized mice, and human lungs. Eighteen samples in total were analyzed from different donors and tissues.
2013-04-04 | E-GEOD-43184 | biostudies-arrayexpress
Project description:CD1c+ dendritic cell activation by Plasmodium falciparum-infected red blood cells
2017-11-11 | GSE89087 | GEO
Project description:ObjectiveTo analyze the potential role of semaphorin 4A (Sema4A) in inflammatory and fibrotic processes involved in the pathology of systemic sclerosis (SSc).MethodsSema4A levels in the plasma of healthy controls (n = 11) and SSc patients (n = 20) were determined by enzyme-linked immunosorbent assay (ELISA). The expression of Sema4A and its receptors in monocytes and CD4+ T cells from healthy controls and SSc patients (n = 6-7 per group) was determined by ELISA and flow cytometry. Th17 cytokine production by CD4+ T cells (n = 5-7) was analyzed by ELISA and flow cytometry. The production of inflammatory mediators and extracellular matrix (ECM) components by dermal fibroblast cells (n = 6) was analyzed by quantitative polymerase chain reaction, ELISA, Western blotting, confocal microscopy, and ECM deposition assay.ResultsPlasma levels of Sema4A, and Sema4A expression by circulating monocytes and CD4+ T cells, were significantly higher in SSc patients than in healthy controls (P < 0.05). Inflammatory mediators significantly up-regulated the secretion of Sema4A by monocytes and CD4+ T cells from SSc patients (P < 0.05 versus unstimulated SSc cells). Functional assays showed that Sema4A significantly enhanced the expression of Th17 cytokines induced by CD3/CD28 in total CD4+ T cells as well in different CD4+ T cell subsets (P < 0.05 versus unstimulated SSc cells). Finally, Sema4A induced a profibrotic phenotype in dermal fibroblasts from both healthy controls and SSc patients, which was abrogated by blocking or silencing the expression of Sema4A receptors.ConclusionOur findings indicate that Sema4A plays direct and dual roles in promoting inflammation and fibrosis, 2 main features of SSc, suggesting that Sema4A might be a novel therapeutic target in SSc.
| S-EPMC6790618 | biostudies-literature