DCATHEROAZMVZ · Dendritic Cells in the Pathogenesis of Atherosclerosis
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2007-01-01 → 2008-12-31
- EU contribution
- €156,625
- Participants
- 1
- Scheme
- EIF
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Results in brief
Final Activity Report Summary - DCATHEROAZMVZ (Dendritic cells in the pathogenesis of atherosclerosis)
In this proposal we set out to investigate the presence and function of antigen-presenting dendritic cells (DC) in atherosclerosis. As a model system of atherosclerosis, apolipoprotein E-deficient mice were used, that develop a hypercholesterolemie and atherosclerotic lesions at prededliction sites. In normal vessels isolated from animals that are not diseased, we could detect a dendritic cell network using multiphoton micrcoscopy. Using CCL17 knock-out, enhanced green fluorescence protein (EGFP) knock-in reporter mice, that allow the visulisation of CCL17-expressing DC, single EGFP+ DC could be detected within atherosclerotic lesions of the aortic root of both CCL17E/- and CCL17E/E apoE-/- mice by immunofluorescence staining and three days after adoptive transfer of CCL17+/- DC by multiphoton-microscopy, demonstrating the recruitment of single DC to atherosclerotic vessels. In addition, in chimeric apo-/- mice with bone marrow from CCL17E/- mice, these EGFP+ cells were demonstrated to originate from the bone marrow. In addition, we were able to demonstrate that the deficience of CCL17 reduced atheroscleritc lesion formation in the aorta and the aortic root of CCL17E/E versus CCL17E/+ apoE-/- mice, accompanied by shift of the immune balance towards an atherprotective cytokine profile and an increase in anti-inflammtory cytokines. These findings not only identify the subpopulation of CCL17+ DC as central immune regulators in atherosclerosis, these data also provide new insights into the immunpathogenesis of atherosclerosis and imply CCL17 as a promising target in the treatment of this disease.
Data: CORDIS, © European Union
Project objective
Atherosclerosis is the main cause of death in the industrial world. The understanding of the pathogenesis has led to the notion of atherosclerosis as a chronic inflammatory disease. The evidence of a network of vascular-associated dendritic cells (DC) in arteries of healthy young individuals, as well as findings demonstrating an infiltration of atherosclerotic plaques where DC accumulation in close contact with macrophages/ monocytes and T-cells implies an important role of DC suggests a functional role of DC, in the activation of the vascular immune system and in the pathogenesis of atherosclerosis. So far the molecular mechanisms regulating the recruitment and causative role of DC in the formation of atherosclerotic plaques remains to be elucidated. DC derives from hematopoietic cells but also peripheral monocytes. So far, several different markers have been used to detect DC in atherosclerotic lesions, however, these are of low specificity.The CCL17 chemokine (also referred to as dendrokine) is expressed only by mature DC. Using an eGFP knock-in, CCL17 knock-out, crossed into the atherosclerosis prone apolipoprotein E deficient (apoE-/-) background, will allow us to specifically study the role of DC in pathological pathways operative in atherosclerosis. The infiltration and localization of DC in atherosclerotic lesions will be studied by detection of GFP-expressing DC in heterozygous CCL17E/+ apoE-/- mice by dual photon microscopy. Double knockout mice will be used to evaluate the role of DC and of their effector chemokines CCL17 in lesion development in native atherosclerosis. Furthermore, in vitro and in vivo assays will be performed to investigate the instruction or modulation of a specific immune response during the initiation and progression of atherosclerotic lesions.
Original text from CORDIS.
Participants
- CARDIOVASCULAR RESEARCH INSTITUTE MAASTRICHT · MAASTRICHTCoordinatorCity levelNetherlands
Links
Data: CORDIS, © European Union