CXCL4 drives fibrosis by promoting several key cellular and molecular processes

• DOI: 10.1016/j.celrep.2021.110189
• Publication Date: 2022-01-04T15:45:29Z
• Authors: Alsya J. Affandi; Tiago Carvalheiro; Andrea Ottria; Judith J. de Haan; Maike A.D. Brans; Maarten M. Brandt; Ralph G. Tieland; Ana P. Lopes; Beatriz Malvar Fe...; Cornelis P.J. Bekker; Maarten van der L...; Maili Zimmermann; Barbara Giovannone; Catharina G.K. Wi...; Samuel Garcia; Michael de Kok; Giuseppina Stifano; Yan Juan Xu; M. Anna Kowalska; Maaike Waasdorp; Caroline Cheng; Susan Gibbs; Saskia C.A. de Jager; Joel A.G. van Roon; Timothy R.D.J. Ra...; Wioleta Marut
• Keywords: 0301 basic medicine; Epithelial-Mesenchymal Transition; systemic sclerosis; Pulmonary Fibrosis; General Biochemistry,Genetics and Molecular Biology; Platelet Factor 4; Cell Line; Bleomycin; Mice; 03 medical and health sciences; SDG 3 - Good Health and Well-being; Human Umbilical Vein Endothelial Cells; Animals; Humans; Myofibroblasts; Lung; Mice, Knockout; Mice, Inbred BALB C; Scleroderma, Systemic; bleomycin; fibrosis; Endothelial Cells; CXCL4; myofibroblast; endothelial-to-mesenchymal transition; Extracellular Matrix; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; inflammation; Collagen; Pericytes

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.