CXCL4-Induced Macrophages: A Novel Therapeutic Target in Human Atherosclerosis?

Atherosclerosis and its consequences (i.e. myocardial infarction and cardiac death) remain the major cause of morbidity and mortality in Western countries (Roger et al. 2011). Despite clinical advances that have substantially improved outcomes in patients suffering from coronary artery disease, including pharmacological interventions (e.g. novel anti platelet therapies, statins, etc.) as well as interventional and surgical therapies (e.g. drug-eluting stents), there is still a huge demand for improved diagnostic tools to identify patients at risk for adverse events as well as therapeutic means to prevent adverse events in these patients. Biomarkers such as high sensitivity CRP (Ridker 2007) or high sensitivity troponin T (Kurz et al. 2011) have brought some improvement in identifying patients requiring more intense treatment; however, the clinical need for better tools remains. An important concept that may help to improve clinical care for patients with coronary artery disease is the inducement of plaque stability. Atherosclerotic lesions can show features of plaque stability or plaque instability (Naghavi et al. 2003a, Naghavi et al. 2003b). Stable plaques are characterized by a thick fibrous cap and a small necrotic core. By contrast, unstable plaques display a thin fibrous cap and a large necrotic core consisting of apoptotic macrophages, foam cells, and smooth muscle cells. Unstable plaques are more likely to rupture, and plaque rupture may subsequently result in thrombosis and occlusion of the vessel leading to a myocardial infarction or stroke. A promising approach to identify potential markers of plaque instability may be the study of atherogenesis on a cellular and molecular level. During the development of atherosclerotic lesions, blood monocytes adhere to the activated endothelium, transmigrate into the subendothelial space, and differentiate towards macrophages, dendritic cells, or foam cells (Galkina & Ley 2009). Among the various leukocyte types involved in atherogenesis, monocytes and monocyte-derived macrophages represent the major fraction. The monocyte-macrophage differentiation process is affected by the extracellular matrix as well as by the combination of chemokines and cytokines representing the micromilieu of the plaque (Shashkin et al. 2005). In addition, cell-cell interactions may also affect the fate of monocytes within the atherosclerotic plaque. Monocyte-derived cells secrete chemokines, cytokines, and other mediators, leading to attraction of other immune cells and thereby promoting plaque progression and plaque instability (Shashkin et al. 2005). While it was initially thought that monocyte-derived macrophages represent a homogenous population