CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitro
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...
Main Authors: | , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2020-09-01
|
Series: | Frontiers in Immunology |
Subjects: | |
Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.02149/full |
_version_ | 1811193127884554240 |
---|---|
author | 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 |
author_facet | 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 |
author_sort | Sandra C. Silva-Cardoso |
collection | DOAJ |
description | 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. |
first_indexed | 2024-04-12T00:03:21Z |
format | Article |
id | doaj.art-e286df9b07224ea08dc328f58bd71e1b |
institution | Directory Open Access Journal |
issn | 1664-3224 |
language | English |
last_indexed | 2024-04-12T00:03:21Z |
publishDate | 2020-09-01 |
publisher | Frontiers Media S.A. |
record_format | Article |
series | Frontiers in Immunology |
spelling | doaj.art-e286df9b07224ea08dc328f58bd71e1b2022-12-22T03:56:11ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-09-011110.3389/fimmu.2020.02149554665CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitroSandra C. Silva-Cardoso0Sandra C. Silva-Cardoso1Weiyang Tao2Weiyang Tao3Chiara Angiolilli4Chiara Angiolilli5Ana P. Lopes6Ana P. Lopes7Cornelis P. J. Bekker8Cornelis P. J. Bekker9Abhinandan Devaprasad10Abhinandan Devaprasad11Barbara Giovannone12Jaap van Laar13Marta Cossu14Marta Cossu15Wioleta Marut16Wioleta Marut17Erik Hack18Rob J. de Boer19Marianne Boes20Marianne Boes21Timothy R. D. J. Radstake22Timothy R. D. J. Radstake23Aridaman Pandit24Aridaman Pandit25Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Dermatology and Allergology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsTheoretical Biology, Utrecht University, Utrecht, NetherlandsCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Pediatrics, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsCenter for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsDepartment of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, NetherlandsFibrosis 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.https://www.frontiersin.org/article/10.3389/fimmu.2020.02149/fullCXCL4dendritic cellsfibrosisgene regulatory networksinflammation |
spellingShingle | 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 CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitro Frontiers in Immunology CXCL4 dendritic cells fibrosis gene regulatory networks inflammation |
title | CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitro |
title_full | CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitro |
title_fullStr | CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitro |
title_full_unstemmed | CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitro |
title_short | CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitro |
title_sort | cxcl4 links inflammation and fibrosis by reprogramming monocyte derived dendritic cells in vitro |
topic | CXCL4 dendritic cells fibrosis gene regulatory networks inflammation |
url | https://www.frontiersin.org/article/10.3389/fimmu.2020.02149/full |
work_keys_str_mv | AT sandracsilvacardoso cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT sandracsilvacardoso cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT weiyangtao cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT weiyangtao cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT chiaraangiolilli cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT chiaraangiolilli cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT anaplopes cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT anaplopes cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT cornelispjbekker cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT cornelispjbekker cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT abhinandandevaprasad cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT abhinandandevaprasad cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT barbaragiovannone cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT jaapvanlaar cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT martacossu cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT martacossu cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT wioletamarut cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT wioletamarut cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT erikhack cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT robjdeboer cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT marianneboes cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT marianneboes cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT timothyrdjradstake cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT timothyrdjradstake cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT aridamanpandit cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro AT aridamanpandit cxcl4linksinflammationandfibrosisbyreprogrammingmonocytederiveddendriticcellsinvitro |