Systemic sclerosis (SSc) is a chronic inflammatory disorder in which excessive fibrosis occurs in all vital organs, leading to profound disability and premature death. The pathogenesis of SSc is still unclear. Although earlier studies focused on fibroblast biology and pro-fibrotic factors, recently evidence advocates an important role of immune cells in the pathogenesis of this disease. In the last few years Prof. Radstake's has focused on immune cell subsets, in particular on plasmacytoid dendritic cells (pDCs), to identify their potential role in SSc. This has led to various landmark observations. Firstly, pDCs were found to secrete high amounts of specific chemokine-CXCL4. Secondly, CXCL4 was found to be closely associated with disease severity and implicated in key immune defects that recapitulate SSc. The current proposal builds further on these key observations and aims at elucidating the underlying mechanisms by which CXCL4 drives SSc by addressing three research topics: 1) identify factors that drive CXCL4 secretion, 2) discover novel functions of CXCL4, 3) determine the role of CXCL4 in vivo. For this purpose I will exploit patient material from a unique SSc cohort, use various state-of-the-art technologies and apply three experimental mouse models.SSc might be the ideal disease to study events that preclude the onset of fibrosis, since both the immune component and typical fibrotic events coincide in this condition. The state-of-the-art know-how, techniques and patient material present at the Laboratory of Translational Research ensure not only a fast and effective dissemination of our results to third parties (pharma) to initiate the development of therapeutic targets, but also the extrapolation to other fibrosing conditions such as idiopathic pulmonary fibrosis etc. Altogether, the current grant provides unique opportunities for me as researcher and research field to show that CXCL4 is an attractive therapeutic target for battling fibrosing conditions.