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 ceils, 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.
| Wolf, Dennis; Ley, Klaus (2015) Waking up the stem cell niche: how hematopoietic stem cells generate inflammatory monocytes after stroke. Circ Res 116:389-92 |
| Ge, Shuwang; Hertel, Barbara; Koltsova, Ekaterina K et al. (2013) Increased atherosclerotic lesion formation and vascular leukocyte accumulation in renal impairment are mediated by interleukin-17A. Circ Res 113:965-74 |
| Koltsova, Ekaterina K; Kim, Gisen; Lloyd, Kathleen M et al. (2012) Interleukin-27 receptor limits atherosclerosis in Ldlr-/- mice. Circ Res 111:1274-85 |
| Koltsova, Ekaterina K; Garcia, Zacarias; Chodaczek, Grzegorz et al. (2012) Dynamic T cell-APC interactions sustain chronic inflammation in atherosclerosis. J Clin Invest 122:3114-26 |
| Galkina, Elena V; Butcher, Matthew; Keller, Susanna R et al. (2012) Accelerated atherosclerosis in Apoe-/- mice heterozygous for the insulin receptor and the insulin receptor substrate-1. Arterioscler Thromb Vasc Biol 32:247-56 |
| Wingender, Gerhard; Hiss, Marcus; Engel, Isaac et al. (2012) Neutrophilic granulocytes modulate invariant NKT cell function in mice and humans. J Immunol 188:3000-8 |
| Doran, Amanda C; Lipinski, Michael J; Oldham, Stephanie N et al. (2012) B-cell aortic homing and atheroprotection depend on Id3. Circ Res 110:e1-12 |
| Koltsova, Ekaterina K; Ley, Klaus (2011) How dendritic cells shape atherosclerosis. Trends Immunol 32:540-7 |
| von Vietinghoff, Sibylle; Koltsova, Ekaterina K; Mestas, Javier et al. (2011) Mycophenolate mofetil decreases atherosclerotic lesion size by depression of aortic T-lymphocyte and interleukin-17-mediated macrophage accumulation. J Am Coll Cardiol 57:2194-204 |
| Ley, Klaus; Miller, Yury I; Hedrick, Catherine C (2011) Monocyte and macrophage dynamics during atherogenesis. Arterioscler Thromb Vasc Biol 31:1506-16 |
Showing the most recent 10 out of 59 publications
