https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=33042127&retmode=xml&tool=Litmetric&email=readroberts32@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09 330421272021050620210506
1664-3224112020Frontiers in immunologyFront ImmunolCXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitro.21492149214910.3389/fimmu.2020.02149Fibrosis is a condition shared by numerous inflammatory diseases. Our incomplete understanding of the molecular mechanisms underlying fibrosis has severely hampered effective drug development. CXCL4 is associated with the onset and extent of fibrosis development in multiple inflammatory and fibrotic diseases. Here, we used monocyte-derived cells as a model system to study the effects of CXCL4 exposure on dendritic cell development by integrating 65 longitudinal and paired whole genome transcriptional and methylation profiles. Using data-driven gene regulatory network analyses, we demonstrate that CXCL4 dramatically alters the trajectory of monocyte differentiation, inducing a novel pro-inflammatory and pro-fibrotic phenotype mediated via key transcriptional regulators including CIITA. Importantly, these pro-inflammatory cells directly trigger a fibrotic cascade by producing extracellular matrix molecules and inducing myofibroblast differentiation. Inhibition of CIITA mimicked CXCL4 in inducing a pro-inflammatory and pro-fibrotic phenotype, validating the relevance of the gene regulatory network. Our study unveils that CXCL4 acts as a key secreted factor driving innate immune training and forming the long-sought link between inflammation and fibrosis.Copyright © 2020 Silva-Cardoso, Tao, Angiolilli, Lopes, Bekker, Devaprasad, Giovannone, van Laar, Cossu, Marut, Hack, de Boer, Boes, Radstake and Pandit.Silva-CardosoSandra CSCCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.TaoWeiyangWCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.AngiolilliChiaraCCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.LopesAna PAPCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.BekkerCornelis P JCPJCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.DevaprasadAbhinandanACenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.GiovannoneBarbaraBDepartment of Dermatology and Allergology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.van LaarJaapJDepartment of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.CossuMartaMCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.MarutWioletaWCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.HackErikECenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.de BoerRob JRJTheoretical Biology, Utrecht University, Utrecht, Netherlands.BoesMarianneMCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.Department of Pediatrics, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.RadstakeTimothy R D JTRDJCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.PanditAridamanACenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.engJournal ArticleResearch Support, Non-U.S. Gov't20200917
SwitzerlandFront Immunol1015609601664-32240MHC class II transactivator protein0Nuclear Proteins0PF4 protein, human0RNA, Small Interfering0Trans-Activators37270-94-3Platelet Factor 4776B62CQ27DecitabineO84C90HH2LPoly I-CIMCells, CulturedCellular Reprogramming TechniquesDNA MethylationDecision TreesDecitabinepharmacologyDendritic CellscytologyFibroblastsFibrosisgeneticsimmunologyGene Regulatory NetworksHumansInflammationgeneticsimmunologyMonocytescytologyMultidimensional Scaling AnalysisNuclear Proteinsantagonists & inhibitorsphysiologyPlatelet Factor 4physiologyPoly I-CpharmacologyRNA InterferenceRNA, Small InterferinggeneticspharmacologyRNA-SeqTrans-Activatorsantagonists & inhibitorsphysiologyTranscriptomeCXCL4dendritic cellsfibrosisgene regulatory networksinflammation202042420208720201012529202010136020215760202011epublish33042127PMC752741510.3389/fimmu.2020.02149Rinkevich Y, Walmsley GG, Hu MS, Maan ZN, Newman AM, Drukker M, et al. . 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