CXCL4 drives fibrosis by promoting several key cellular and molecular processes.

Alsya J Affandi,Wioleta Marut,Maike A.D Brans,Michael De Kok,Ralph G Tieland,Tiago Carvalheiro,Maarten Van Der Linden,Maarten M Brandt,Caroline Cheng,Giuseppina Stifano,Maili Zimmermann,Susan Gibbs,Barbara Giovannone,Judith J De Haan,Saskia C.A De Jager,M Anna Kowalska,Andrea Ottria,Maaike Waasdorp,Joël A G Van Roon ,Yan Xu ,Timothy R D J Radstake ,Cornelis P J Bekker ,Beatriz Fernández ,Samuel García ,Ana P Lopes ,Catharina G K Wichers

doi:10.1016/j.celrep.2021.110189

Abstract

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. Invitro, 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.

Highlights

In fibrotic disorders, an excessive deposition of extracellular matrix (ECM) leads to obliteration of the original tissue architecture and function (Rockey et al, 2015)
CXCL4 is increased in inflammatory and fibrotic conditions CXCL4 has been shown to be increased in systemic sclerosis (SSc) skin and a bleomycin-induced skin fibrosis model, the most widely accepted animal model for SSc (Ah Kioon et al, 2018)
Because CXCL4 has been implicated in other fibrotic diseases (Zaldivar et al, 2010), we utilized the scleroderma-like graft versus host disease model (Scl-GvHD) to induce skin fibrosis and the model of pressure overload-induced cardiac fibrosis by transverse aortic constriction (TAC) to further examine the notion that increased levels of CXCL4 are a generalized phenomenon in fibrosis

Summary

Introduction

An excessive deposition of extracellular matrix (ECM) leads to obliteration of the original tissue architecture and function (Rockey et al, 2015). During this process, many ECM components are produced by activated myofibroblasts, characterized by de novo a-smooth muscle actin (a-SMA) expression (Hinz et al, 2007). Myofibroblasts are required for physiological tissue repair mechanisms such as wound healing, their persistence can lead to development of fibrosis The origin of these cells was initially assumed to be tissue-resident fibroblasts, but other cell types can give rise to formation of myofibroblasts (myofibroblast transformation [MT]). The transformation of myofibroblasts from precursor cells is thought to be driven mainly by transforming growth factor b (TGF-b), but other fibrogenic cytokines derived from immune cells can contribute to this process (Kendall and Feghali-Bostwick, 2014; Lafyatis, 2014)

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