To investigate the role of CXCL4 in activation of macrophages in vitro and in vivo
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE210105 | GEO | 2023/07/29
REPOSITORIES: GEO
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2020-06-01 | GSE115487 | GEO
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)
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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)
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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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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.
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Project description:To investigate the function of RIPK3 in regulation of IFN response and inflammatory response in human monocytes stimulated with CXCL4 and TLR8, We blocks (CXCL4 + TLR8)-induced pyroptosis and RIPK3 activation using necrosulfonamide (NSA, 5 µM) and GSK'872 (10 µM) and measure gene expression genome-wide with RNA-seq.
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Project description:Plasmacytoid dendritic cells (pDCs) infiltrate the skin, chronically produce type I interferon (IFN-I) and promote skin lesions and fibrosis in autoimmune patients. However, what controls their activation in the skin is unknown. Here, we report that increased stiffness, characteristic of the skin microenvironment, inhibits the production of IFN-I by TLR-activated pDCs. Mechanistically, mechanosensing activates stress pathways including the transcription factor NRF2, which, by triggering the pentose phosphate pathway, rewires glycolysis and reduces pyruvate levels, a product necessary for pDC responses. Modulating NRF2 expression in skin-infiltrating pDCs controlled the IFN-I response, leading to either resolution or the sustained activation of pathologic IFN-I pathway in the skin. Moreover, we observed that CXCL4, a pro-fibrotic chemokine that is elevated in fibrotic skin, was able to overcome stiffness-mediated IFN-I inhibition, allowing chronic IFN-I responses by pDCs in the skin. Furthermore, in the skin of patients with systemic sclerosis (SSc), although NRF2 was induced in skin-infiltrating pDCs as compared to blood pDCs, the IFN-response was maintained. Hence, these data identify a novel regulatory mechanism exerted by the skin microenvironment and identify points of dysregulation of this mechanism in patients with skin inflammation and fibrosis.
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Project description:Plasmacytoid dendritic cells (pDCs) infiltrate the skin, chronically produce type I interferon (IFN-I) and promote skin lesions and fibrosis in autoimmune patients. However what controls their activation in the skin is unknown. Here, we report that increased stiffness, characteristic of the skin microenvironment, inhibits the production of IFN-I by TLR-activated pDCs. Mechanistically, mechanosensing activates stress pathways including the transcription factor NRF2, which, by triggering the pentose phosphate pathway, rewires glycolysis and reduces pyruvate levels, a product necessary for pDC responses. Modulating NRF2 expression in skin-infiltrating pDCs controlled the IFN-I response, leading to either resolution or the sustained activation of pathologic IFN-I pathway in the skin. Moreover, we observed that CXCL4, a pro-fibrotic chemokine that is elevated in fibrotic skin, was able to overcome stiffness-mediated IFN-I inhibition, allowing chronic IFN-I responses by pDCs in the skin. Furthermore, in the skin of patients with systemic sclerosis (SSc), although NRF2 was induced in skin-infiltrating pDCs as compared to blood pDCs, the IFN-response was maintained. Hence, these data identify a novel regulatory mechanism exerted by the skin microenvironment and identify points of dysregulation of this mechanism in patients with skin inflammation and fibrosis.
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