TY - JOUR
T1 - CXCL4 drives fibrosis by promoting several key cellular and molecular processes
AU - Affandi, Alsya J.
AU - Carvalheiro, Tiago
AU - Ottria, Andrea
AU - de Haan, Judith J.
AU - Brans, Maike A. D.
AU - Brandt, Maarten M.
AU - Tieland, Ralph G.
AU - Lopes, Ana P.
AU - Fernandez, Beatriz Malvar
AU - Bekker, Cornelis P. J.
AU - van der Linden, Maarten
AU - Zimmermann, Maili
AU - Giovannone, Barbara
AU - Wichers, Catharina G. K.
AU - Garcia, Samuel
AU - de Kok, Michael
AU - Stifano, Giuseppina
AU - Xu, Yan Juan
AU - Kowalska, M. Anna
AU - Waasdorp, Maaike
AU - Cheng, Caroline
AU - Gibbs, Susan
AU - de Jager, Saskia C. A.
AU - van Roon, Joel A. G.
AU - Radstake, Timothy R. D. J.
AU - Marut, Wioleta
N1 - Funding Information: A.J.A. was supported by the Dutch Arthritis Association (Reumafonds grant NR-10-1-301 ) and the Netherlands Organisation for Scientific Research (NWO, Mosaic grant 017.008.014 ). T.C. was supported by a grant from the Portuguese National Funding Agency for Science, Research and Technology : Fundação para a Ciência e a Tecnologia [ SFRH/BD/93526/2013 ]. T.R.D.J.R and J.A.G.v.R. received funding from an European Research Council (ERC) Starting Grant ( ERC-2011-StG , Circumvent). W.M. obtained funding from the Marie Curie Intra-European Fellowship (Proposal number: 624871) and from the NWO VENI (grant number 91919149 ). We thank Mike DiMarzio, Giuseppina A. Farina (Boston University School of Medicine), Sarita Hartgring, Aniek Meijers, Karin de Cortie, Wouter van Leeuwen, Dirk-Jan Heijnen, Enric Mocholi-Gimeno, and Christian van Dijk (University Medical Center Utrecht) for technical advice, support, and expertise. We also thank Kris A. Reedquist for critical review of the manuscript. Publisher Copyright: © 2021 The Authors
PY - 2022/1/4
Y1 - 2022/1/4
N2 - Fibrosis is a major cause of mortality worldwide, characterized by myofibroblast activation and excessive extracellular matrix deposition. Systemic sclerosis is a prototypic fibrotic disease in which CXCL4 is increased and strongly correlates with skin and lung fibrosis. Here we aim to elucidate the role of CXCL4 in fibrosis development. CXCL4 levels are increased in multiple inflammatory and fibrotic mouse models, and, using CXCL4-deficient mice, we demonstrate the essential role of CXCL4 in promoting fibrotic events in the skin, lungs, and heart. Overexpressing human CXCL4 in mice aggravates, whereas blocking CXCL4 reduces, bleomycin-induced fibrosis. Single-cell ligand-receptor analysis predicts CXCL4 to affect endothelial cells and fibroblasts. In vitro, we confirm that CXCL4 directly induces myofibroblast differentiation and collagen synthesis in different precursor cells, including endothelial cells, by stimulating endothelial-to-mesenchymal transition. Our findings identify a pivotal role of CXCL4 in fibrosis, further substantiating the potential role of neutralizing CXCL4 as a therapeutic strategy.
AB - Fibrosis is a major cause of mortality worldwide, characterized by myofibroblast activation and excessive extracellular matrix deposition. Systemic sclerosis is a prototypic fibrotic disease in which CXCL4 is increased and strongly correlates with skin and lung fibrosis. Here we aim to elucidate the role of CXCL4 in fibrosis development. CXCL4 levels are increased in multiple inflammatory and fibrotic mouse models, and, using CXCL4-deficient mice, we demonstrate the essential role of CXCL4 in promoting fibrotic events in the skin, lungs, and heart. Overexpressing human CXCL4 in mice aggravates, whereas blocking CXCL4 reduces, bleomycin-induced fibrosis. Single-cell ligand-receptor analysis predicts CXCL4 to affect endothelial cells and fibroblasts. In vitro, we confirm that CXCL4 directly induces myofibroblast differentiation and collagen synthesis in different precursor cells, including endothelial cells, by stimulating endothelial-to-mesenchymal transition. Our findings identify a pivotal role of CXCL4 in fibrosis, further substantiating the potential role of neutralizing CXCL4 as a therapeutic strategy.
KW - CXCL4
KW - bleomycin
KW - endothelial-to-mesenchymal transition
KW - fibrosis
KW - inflammation
KW - myofibroblast
KW - systemic sclerosis
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U2 - https://doi.org/10.1016/j.celrep.2021.110189
DO - https://doi.org/10.1016/j.celrep.2021.110189
M3 - Article
C2 - 34986347
SN - 2211-1247
VL - 38
JO - Cell Reports
JF - Cell Reports
IS - 1
M1 - 110189
ER -
