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Final Report Summary - EXCELSIOR (The Expression of CXC chemokine ligand 4 in Systemic Sclerosis and its Role in the regulation of immune and fibrotic responses)

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs, preceded by vascular and immune dysfunction. SSc is usually preceded by Raynaud’s phenomenon (white/purple discoloured fingers) and our group demonstrated that pDCs from individuals with Raynaud’s phenomenon that progress into SSc have troubles dealing with hypoxic events associated with Raynaud’s phenomenon.
The mechanisms responsible for SSc initiation are largely unknown, but recent work from our group and others demonstrated that an aberrant immune system is central to its pathogenesis. Our recent data point at pDCs as the cell type responsible for initiating the fibrotic process observed in SSc patients.These cells are highly increased and activated in SSc and produce high levels of the chemokine CXCL4, suggested to be a pathogenic hallmark of this disease. This study investigated what is the driving factor for CXCL4 secretion by SSc pDCs and investigated the function of CXCL4 in vitro and in vivo.
Dr. Marut has identyfied the factor resposible for the secretion of CXCL4 from pDCs. Hypoxia together with CpG-C stimulation induced secretion of CXCL4 chemokine from pDCs, while other cytokines produced by these cells were unchanged. Moreover, increased CXCL4 production by pDCs after hypoxia and CpG-C exposure was correlating with increased production of mitochondrial reactive oxygene species (mt-ROS) and increased glycolisis. Blocking of glycolisis and mtROS also reduced CXCL4 production, indicating that hypoxia induce CXCL4 secretion in pDCs via increased glycolisis and mtROS production.
Furthermore, dr. Marut investiagted the profibrotic properties of CXCL4 in vitro and in vivo. Interestingly, she found that CXCL4 chemokine has very strong profibrotic properties, simillar to the strongest profibrotic cytokine known so far in SSc - TGFb. She investigated profibrotic properties in in vitro system by looking at fibroblasts, endothelial cells, epithelial cells and at endothelial/pericytes co-coulture. She saw that CXCL4 induce fibroblasts activation and proliferation, as well as collagen production. Moreover, CXCL4 induce Endo-MT and EMT. She also looked at the role of CXCL4 in immune cells, mainly monocytes and moDCs. Both of the cell types produced a lot of proinflammatory cytokines after exposure to CXCL4. In vivo, she determined the role of CXCL4 by looking at CXCL4 -/- mice versus wild type mice. She looked at the respose of CXCL4 -/- vs WT mice mainly in the bleomycin induced fibrosis/SSc like phenotype model. Bleomycin is a well known mice model of SSc that allowed us to investigate inflammation, skin and lung fibrosis, as well as vascular dysfunction - all aspects present in human SSc.
Both, in vitro and in vivo results obtained by dr. Marut indicate that CXCL4 plays a crucial role in the induction of inflammation, fibrosis of the lung and skin, and endothelial dysfunction - placing CXCL4 in the center of SSc pathogenesis.
SSc is a severe fibrotic disease with high mortality risk. No effective therapeutic intervention exists today: Most SSc patients do not respond to medications for related auto-immune diseases and current therapies have severe side-effects and high mortality rates. This study uncovered-CXCL4 as a novel drug target and possibility for development of effective treatment for SSc patients. Moreover, this project enable a broad and general understanding of how small chemokine-CXCL4 can initiate this disease. Finally, since SSc is the prototype of fibrotic disease and that the project investigated profibrotic function of CXCL4 chemokine, the unique knowledge and therapeutic opportunities gained with this study will impact the full spectrum of fibrotic conditions.

Contact

A.M. Van der Linden, (Project Controller)
Tel.: +31 88 7551994
E-mail
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