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.
Bibliographical noteFunding 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.
© 2021 The Authors