CXCL4 drives fibrosis by promoting several key cellular and molecular processes

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 Fernández, Cornelis P J Bekker, Maarten van der Linden, Maili Zimmermann, Barbara Giovannone, Catharina G K Wichers, Samuel Garcia, Michael de Kok, Giuseppina Stifano, Yan Juan Xu, M Anna Kowalska, Maaike WaasdorpCaroline Cheng, Susan Gibbs, Saskia C A de Jager, Joel A G van Roon, Timothy R D J Radstake, Wioleta Marut

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)110189
TijdschriftCell reports
Volume38
Nummer van het tijdschrift1
DOI's
StatusGepubliceerd - 4 jan. 2022

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