Final Report Summary - CIRCUMVENT (Closing in on Runx3 and CXCL4 to open novel avenues for therapeutic intervention in systemic sclerosis)
In this project we examined the role of CXCL4 in fibrosis. We have demonstrated unequivocally that CXCL4 plays an essential role in many processes that participate in fibrosis - or linking inflammation with fibrosis - which hitherto was a unknown process. For instance, we show that CXCL4 activates fibroblasts, induces myofibroblast transition, epithelial to mesenchymal transition, fibrocyte activation, T cell activation as well as dendritic cell activation - all processes relevant in systemic sclerosis the archetypical fibrotic disease. The role of CXCL4 as next confirmed by performing several models (Bleomycine, TAC) for fibrosis in a CXCL4 knockout background. Intrguingly, KO of CXCL4 almost completely abrogated fibrosis of the skin, lung and gut as well as the heart in these models respectively. In a parallel project, we investigated the role of CXCL4 in genetic and epigenetic changes in inflammatory macrophages thereby possibly driving direct extra cellular matrix formation. here we show that CXCL4 itself induces the formation of ECM by inflammatory macrophages as well as that these cells stimulate myofibroblast activation indirectly via the secretion of pro-fibrotic mediators. This latter part of research reveals that inflammatory macrophages themselves and directly contribute to fibrosis. Altogether, we demonstrate the essential role of CXCL4 in fibrosis providing evidence for CXCL4 as a potential therapeutic target for SSc as well as other fibrosing conditions.