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CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitro

  • Silva-Cardoso, Sandra C.1, 2
  • Tao, Weiyang1, 2
  • Angiolilli, Chiara1, 2
  • Lopes, Ana P.1, 2
  • Bekker, Cornelis P. J.1, 2
  • Devaprasad, Abhinandan1, 2
  • Giovannone, Barbara3
  • van Laar, Jaap2
  • Cossu, Marta1, 2
  • Marut, Wioleta1, 2
  • Hack, Erik1
  • de Boer, Rob J.4
  • Boes, Marianne1, 5
  • Radstake, Timothy R. D. J.1, 2
  • Pandit, Aridaman1, 2
  • 1 Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht , (Netherlands)
  • 2 Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht , (Netherlands)
  • 3 Department of Dermatology and Allergology, University Medical Center Utrecht, Utrecht University, Utrecht , (Netherlands)
  • 4 Theoretical Biology, Utrecht University, Utrecht , (Netherlands)
  • 5 Department of Pediatrics, University Medical Center Utrecht, Utrecht University, Utrecht , (Netherlands)
Published Article
Frontiers in Immunology
Frontiers Media SA
Publication Date
Sep 17, 2020
DOI: 10.3389/fimmu.2020.02149
PMID: 33042127
PMCID: PMC7527415
PubMed Central


Fibrosis 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.

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