CXCL4 in atherosclerosis: possible roles in monocyte arrest and macrophage foam cell formation.

Thromb Haemost 2007; 98: 917–918 In this issue of Thrombosis and Haemostasis, Sachais et al. demonstrate a critical role for platelet factor 4 (CXCL4) in the development of atherosclerosis (1). In two mouse models, CXCL4 deficiency induced by gene targeting and homologous recombination resulted in reduction of atherosclerotic lesion size without affecting platelet activation or changing cholesterol levels. CXCL4 was one of the first chemokines to be discovered (2), but its role has remained largely enigmatic. The presence of platelets in atherosclerotic lesions is well documented (3). Based on mouse models, a role of platelet-derived chemokines for monocyte recruitment to the arterial wall has been postulated previously (4, 5). CXCL4 is also found in atherosclerotic lesions of human carotid arteries (6), suggesting a role in atherogenesis. CXCL4 has a number of biological effects, which depend on the target cell type. CXCL4 can induce chemokine or cytokine release and inhibit or promote cell differentiation (7). At least two of these effects are likely to be important during the development of atherosclerotic plaque (Fig.1). CXCL4 has been shown to play a role in monocyte recruitment to the arterial wall. Monocytes are recruited to atherosclerotic lesions in a cascade-like fashion (8), and platelets promote their arrest and recruitment (3–5). CXCL4 interacts with another chemokine, CCL5, also known as RANTES (regulated on activation normal T-cell expressed and secreted). Whereas CXCL4 alone does not affect monocyte arrest on activated endothelial cells under flow, the combination of CXCL4 with CCL5 results in an effect greater than CCL5 alone (9). Three possible explanations have been discussed for this finding: CXCL4 may form heterodimers with CCL5 and thereby increase CCL5 binding to monocytes by supplying additional binding sites, or dimerization of CXCL4 with CCL5 may induce heterodimerization of chemokine receptors, which might modulate intracellular signaling. Alternatively, CXCL4 signaling might enhance CCL5-dependent effects, e.g. by a common pathway involving p38 mitogen-activated kinase in monocytes (9). The exact mechanisms, however, have still to be elucidated. CXCL4 may also increase atherogenesis by promoting differentiation of monocytes into macrophages and foam cells (10). Consistent with this, Sachais et al. demonstrate localization of CXCL4 in murine atherosclerotic plaque close to foam cells. It is known that macrophages differentiated from monocytes under the influence of CXCL4 are in some respect different from those differentiated in the presence of M-CSF (11). M-CSF has been clearly demonstrated to play a crucial role in atherogenesis as demonstrated in M-CSF deficient op/op mice (12). During mac-