Frontiers in Immunology (Sep 2020)
CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitro
- Sandra C. Silva-Cardoso,
- Sandra C. Silva-Cardoso,
- Weiyang Tao,
- Weiyang Tao,
- Chiara Angiolilli,
- Chiara Angiolilli,
- Ana P. Lopes,
- Ana P. Lopes,
- Cornelis P. J. Bekker,
- Cornelis P. J. Bekker,
- Abhinandan Devaprasad,
- Abhinandan Devaprasad,
- Barbara Giovannone,
- Jaap van Laar,
- Marta Cossu,
- Marta Cossu,
- Wioleta Marut,
- Wioleta Marut,
- Erik Hack,
- Rob J. de Boer,
- Marianne Boes,
- Marianne Boes,
- Timothy R. D. J. Radstake,
- Timothy R. D. J. Radstake,
- Aridaman Pandit,
- Aridaman Pandit
Affiliations
- Sandra C. Silva-Cardoso
- Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Sandra C. Silva-Cardoso
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Weiyang Tao
- Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Weiyang Tao
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Chiara Angiolilli
- Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Chiara Angiolilli
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Ana P. Lopes
- Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Ana P. Lopes
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Cornelis P. J. Bekker
- Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Cornelis P. J. Bekker
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Abhinandan Devaprasad
- Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Abhinandan Devaprasad
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Barbara Giovannone
- Department of Dermatology and Allergology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Jaap van Laar
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Marta Cossu
- Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Marta Cossu
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Wioleta Marut
- Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Wioleta Marut
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Erik Hack
- Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Rob J. de Boer
- Theoretical Biology, Utrecht University, Utrecht, Netherlands
- Marianne Boes
- Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Marianne Boes
- Department of Pediatrics, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Timothy R. D. J. Radstake
- Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Timothy R. D. J. Radstake
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Aridaman Pandit
- Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Aridaman Pandit
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- DOI
- https://doi.org/10.3389/fimmu.2020.02149
- Journal volume & issue
-
Vol. 11
Abstract
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.
Keywords
