Atherosclerosis is a chronic inflammatory disease of the arterial wall. Monocyte recruitment is an early and necessary step in atherogenesis. Blood monocytes roll on and adhere to lesion-prone areas such as the carotid sinus, a site that is responsible for strokes. These interactions require adhesion molecules and the chemokines CXCL1-3 and CCL5. Some of these pro-inflammatory chemokines bind to Duffy antigen receptor for chemokines (DARC). DARC is expressed on endothelial cells, where it may support chemokine presentation to rolling leukocytes, and on red blood cells, where it is thought to serve as a chemokine sink. We hypothesize that modulating inflammatory chemokine presentation by DARC influences the recruitment of monocytes and hence atherosclerosis. Once in the vessel wall, monocytes are thought to differentiate into dendritic cells, macrophages, and foam cells. By flow cytometry-based analysis of the normal and atherosclerotic aorta, we have now found that macrophages and dendritic cells are present in the aortic wall already under normal baseline conditions, and macrophage content is increased during atherogenesis. Others have shown that blood monocytes in mice and humans encompass pro-inflammatory and resident- type monocytes, which express low and high levels of the chemokine receptor CX3CR1, respectively. We hypothesize that these two types of blood monocytes differentially enter the arterial wall during atherogenesis and become macrophages, dendritic cells and foam cells. To test these hypotheses, we propose the following three specific aims: (1) To address which monocyte subsets gain access to atherosclerosis-prone sites, we use mice in which CXR3CR1-high and -low monocytes can be distinguished by intravital microscopy, autoperfused flow chamber assays, and flow cytometry. (2) To test whether monocyte subsets defined by CX3CR1 expression differentially contribute to the formation of macrophages, dendritic cells and foam cells in the vessel wall, we use bone marrow transplantation. (3) To test how modulation of inflammatory cytokines by the Duffy antigen receptor DARC influences leukocyte content of the vessel wall with and without atherosclerosis, we will use DARC-/-apoE-/- double knockout mice and bone marrow transplantation. The proposed work may enable the design of interventions into the chemokine network to stabilize atherosclerotic plaques by reducing their content of inflammatory cells.
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