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.
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.