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CXCL4 links inflammation and fibrosis through transcriptional and epigenetic reprogramming of inflammatory monocyte-derived cells [DNA methylation]

ABSTRACT: Fibrosis is a condition shared by numerous inflammatory diseases. The molecular mechanisms underlying fibrosis have remained incompletely understood severely hampering drug development. CXCL4 is associated with the onset and extent of fibrosis development in systemic sclerosis (SSc), a prototypic inflammatory and fibrotic disease. Here, we integrated 65 paired sequential whole genome transcriptional and methylation profiles from monocyte-derived cells as they respond to CXCL4 exposure. Using data-driven gene regulatory network analyses, we demonstrate that CXCL4 dramatically alters monocyte differentiation trajectory inducing a novel pro-inflammatory and pro-fibrotic phenotype mediated via key regulators such as CIITA and IRF8. Importantly, these CXCL4 exposed pro-inflammatory cells trigger a fibrosis cascade by directly producing ECM molecules and by inducing myofibroblast differentiation. Underscoring the computationally identified gene regulatory network, inhibition of CIITA mimicked CXCL4 inducing pro-inflammatory and pro-fibrotic phenotype. Our study uncovers CXCL4 as the endogenous ligand driving innate immune training and forming the long-sought link between inflammation and fibrosis. Correspondence to: Prof. Timothy RDJ Radstake (T.R.D.J.Radstake@umcutrecht.nl) and Dr. Aridaman Pandit (A.Pandit@umcutrecht.nl)

ORGANISM(S): Homo sapiens

PROVIDER: GSE115201 | GEO | 2020/06/01

REPOSITORIES: GEO

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CXCL4 links inflammation and fibrosis through transcriptional and epigenetic reprogramming of inflammatory monocyte-derived cells [RNA-seq]

Project description:Fibrosis is a condition shared by numerous inflammatory diseases. The molecular mechanisms underlying fibrosis have remained incompletely understood severely hampering drug development. CXCL4 is associated with the onset and extent of fibrosis development in systemic sclerosis (SSc), a prototypic inflammatory and fibrotic disease. Here, we integrated 65 paired sequential whole genome transcriptional and methylation profiles from monocyte-derived cells as they respond to CXCL4 exposure. Using data-driven gene regulatory network analyses, we demonstrate that CXCL4 dramatically alters monocyte differentiation trajectory inducing a novel pro-inflammatory and pro-fibrotic phenotype mediated via key regulators such as CIITA and IRF8. Importantly, these CXCL4 exposed pro-inflammatory cells trigger a fibrosis cascade by directly producing ECM molecules and by inducing myofibroblast differentiation. Underscoring the computationally identified gene regulatory network, inhibition of CIITA mimicked CXCL4 inducing pro-inflammatory and pro-fibrotic phenotype. Our study uncovers CXCL4 as the endogenous ligand driving innate immune training and forming the long-sought link between inflammation and fibrosis. Correspondence to: Prof. Timothy RDJ Radstake (T.R.D.J.Radstake@umcutrecht.nl) and Dr. Aridaman Pandit (A.Pandit@umcutrecht.nl)

2020-06-01 | GSE115487 | GEO

CXCL4 links inflammation and fibrosis through transcriptional and epigenetic reprogramming of inflammatory monocyte-derived cells

Project description:Fibrosis is a condition shared by numerous inflammatory diseases. The molecular mechanisms underlying fibrosis have remained incompletely understood severely hampering drug development. CXCL4 is associated with the onset and extent of fibrosis development in systemic sclerosis (SSc), a prototypic inflammatory and fibrotic disease. Here, we integrated 65 paired sequential whole genome transcriptional and methylation profiles from monocyte-derived cells as they respond to CXCL4 exposure. Using data-driven gene regulatory network analyses, we demonstrate that CXCL4 dramatically alters monocyte differentiation trajectory inducing a novel pro-inflammatory and pro-fibrotic phenotype mediated via key regulators such as CIITA and IRF8. Importantly, these CXCL4 exposed pro-inflammatory cells trigger a fibrosis cascade by directly producing ECM molecules and by inducing myofibroblast differentiation. Underscoring the computationally identified gene regulatory network, inhibition of CIITA mimicked CXCL4 inducing pro-inflammatory and pro-fibrotic phenotype. Our study uncovers CXCL4 as the endogenous ligand driving innate immune training and forming the long-sought link between inflammation and fibrosis. This SuperSeries is composed of the SubSeries listed below. Correspondence to: Prof. Timothy RDJ Radstake (T.R.D.J.Radstake@umcutrecht.nl) and Dr. Aridaman Pandit (A.Pandit@umcutrecht.nl)

2020-06-01 | GSE115488 | GEO

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Project description:To gain a comprehensive understanding of gene regulation in CXCL4 and TLR8 signaling crosstalk, we treated primary human blood monocytes with CXCL4 and TLR8 ssRNA ligand ORN8L for 6 h and performed transcriptomic analysis via RNA-seq. We observed that CXCL4 interacted with TLR8 ssRNA ligand and triggered inflammatory cytokine storm including IL6, IL12p40, TNF and IFNβ, and pro-fibrotic gene expression and activated NLRP3 inflammasome leading to interleukin-1β (IL-1β) secretion and pyroptosis in human blood monocytes.

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To investigate the role of CXCL4 in activation of macrophages in vitro and in vivo

Project description:CXCL4 activates myeloid cells and augments endosomal TLR responses contributing to the pathogenesis of inflammatory and fibrotic diseases. However, the underlying mechanisms are not well defined because the receptor(s) that mediates CXCL4 inflammatory responses is not known and downstream signaling pathways leading to gene induction are not well characterized. Here we report that CXCL4 activates inflammatory and tissue repair/fibrotic gene expression in human primary macrophages ex vivo and regulates macrophage skin infiltration and promotes skin wound healing in vivo.

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CXCL4 induces a unique transcriptome in monocyte-derived macrophages

Project description:Human blood monocytes were differentiated over six days with either 100 ng/ml M-CSF or 1 umol/l CXCL4 In atherosclerotic arteries, blood monocytes differentiate to macrophages in the presence of growth factors like macrophage colony-stimulation factor (MCSF) and chemokines like platelet factor 4 (CXCL4). To compare the gene expression signature of CXCL4-induced macrophages with MCSF-induced macrophages or macrophages polarized with IFN-Î³/LPS (M1) or IL-4 (M2), we cultured primary human peripheral blood monocytes for six days. mRNA expression was measured by Affymetrix gene chips and differences were analyzed by Local Pooled Error test, Profile of Complex Functionality and Gene Set Enrichment Analysis. 375 genes were differentially expressed between MCSF- and CXCL4-induced macrophages, 206 of them overexpressed in CXCL4 macrophages coding for genes implicated in the inflammatory/immune response, antigen processing/presentation, and lipid metabolism. CXCL4-induced macrophages overexpressed some M1 and M2 genes and the corresponding cytokines at the protein level, however, their transcriptome clustered with neither M1 nor M2 transcriptomes. They almost completely lost the ability to phagocytose zymosan beads. Genes linked to atherosclerosis were not consistently up- or downregulated. Scavenger receptors showed lower and cholesterol efflux transporters higher expression in CXCL4- than MCSF-induced macrophages, resulting in lower LDL content. We conclude that CXCL4 induces a unique macrophage transcriptome distinct from known macrophage types, defining a new macrophage differentiation that we propose to call M4. two MCSF samples and two CXCL4 samples

2010-03-07 | E-GEOD-20484 | biostudies-arrayexpress

CXCL4 links inflammation and fibrosis through transcriptional and epigenetic reprogramming of inflammatory monocyte-derived cells

Project description:CXCL4 links inflammation and fibrosis through transcriptional and epigenetic reprogramming of inflammatory monocyte-derived cells

| PRJNA475245 | ENA

CXCL4 induces a unique transcriptome in monocyte-derived macrophages

Project description:Human blood monocytes were differentiated over six days with either 100 ng/ml M-CSF or 1 umol/l CXCL4 In atherosclerotic arteries, blood monocytes differentiate to macrophages in the presence of growth factors like macrophage colony-stimulation factor (MCSF) and chemokines like platelet factor 4 (CXCL4). To compare the gene expression signature of CXCL4-induced macrophages with MCSF-induced macrophages or macrophages polarized with IFN-γ/LPS (M1) or IL-4 (M2), we cultured primary human peripheral blood monocytes for six days. mRNA expression was measured by Affymetrix gene chips and differences were analyzed by Local Pooled Error test, Profile of Complex Functionality and Gene Set Enrichment Analysis. 375 genes were differentially expressed between MCSF- and CXCL4-induced macrophages, 206 of them overexpressed in CXCL4 macrophages coding for genes implicated in the inflammatory/immune response, antigen processing/presentation, and lipid metabolism. CXCL4-induced macrophages overexpressed some M1 and M2 genes and the corresponding cytokines at the protein level, however, their transcriptome clustered with neither M1 nor M2 transcriptomes. They almost completely lost the ability to phagocytose zymosan beads. Genes linked to atherosclerosis were not consistently up- or downregulated. Scavenger receptors showed lower and cholesterol efflux transporters higher expression in CXCL4- than MCSF-induced macrophages, resulting in lower LDL content. We conclude that CXCL4 induces a unique macrophage transcriptome distinct from known macrophage types, defining a new macrophage differentiation that we propose to call M4.

2010-03-01 | GSE20484 | GEO

CXCL4 links inflammation and fibrosis through transcriptional and epigenetic reprogramming of inflammatory monocyte-derived cells [DNA methylation]

Project description:CXCL4 links inflammation and fibrosis through transcriptional and epigenetic reprogramming of inflammatory monocyte-derived cells [DNA methylation]

| PRJNA474103 | ENA

CXCL4 links inflammation and fibrosis through transcriptional and epigenetic reprogramming of inflammatory monocyte-derived cells [RNA-seq]

Project description:CXCL4 links inflammation and fibrosis through transcriptional and epigenetic reprogramming of inflammatory monocyte-derived cells [RNA-seq]

| PRJNA475247 | ENA

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