Chemokine Receptor CCR2 Expression and Monocyte Chemoattractant Protein-1–Mediated Chemotaxis in Human Monocytes

Abstract

Abstract-The subendothelial accumulation of macrophage-derived foam cells is one of the hallmarks of atherosclerosis. The recruitment of monocytes to the intima requires the interaction of locally produced chemokines with specific cell surface receptors, including the receptor (CCR2) for monocyte chemoattractant protein-1 (MCP-1). We have previously reported that monocyte CCR2 gene expression and function are effectively downregulated by proinflammatory cytokines. In this study we identified low density lipoprotein (LDL) as a positive regulator of CCR2 expression. Monocyte CCR2 expression was dramatically increased in hypercholesterolemic patients compared with normocholesterolemic controls. Similarly, incubation of human THP-1 monocytes with LDL induced a rapid increase in CCR2 mRNA and protein. By 24 hours the number of cell surface receptors was doubled, causing a 3-fold increase in the chemotactic response to MCP-1. The increase in CCR2 expression and chemotaxis was promoted by native LDL but not by oxidized LDL. Oxidized LDL rapidly downregulated CCR2 expression, whereas reductively methylated LDL, which does not bind to the LDL receptor, had only modest effects on CCR2 expression. A neutralizing anti-LDL receptor antibody prevented the effect of LDL, suggesting that binding and internalization of LDL were essential for CCR2 upregulation. The induction of CCR2 expression appeared to be mediated by LDL-derived cholesterol, because cells treated with free cholesterol also showed increased CCR2 expression. These data suggest that elevated plasma LDL levels in conditions such as hypercholesterolemia enhance monocyte CCR2 expression and chemotactic response and potentially contribute to increased monocyte recruitment to the vessel wall in chronic inflammation and atherogenesis. (Arterioscler Thromb Vasc Biol. 1998;18:1983-1991.)

Glycated LDL increases monocyte CC chemokine receptor 2 expression and monocyte chemoattractant protein-1-mediated chemotaxis

“…Our preliminary data showed that oxidized LDL reduced MCP-1-mediated chemotaxis compared with LDL, a result compatible with previous reports showing that oxidized LDL caused a rapid reduction of CCR2 expression in monocytes, rendering these cells non-responsive to MCP-1 [25,37]. Our findings suggest differing cellular responses to AGE-LDL and oxidized LDL.…”

Up-Regulated Expression of the CXCR2 Ligand KC/GRO-α in Atherosclerotic Lesions Plays a Central Role in Macrophage Accumulation and Lesion Progression

“…6 Furthermore, marked hyperlipidemia did not affect mouse monocyte CXCR2 expression in peripheral blood, in contrast to the capacity of hyperlipidemia to up-regulate both monocyte CCR2 expression and adhesion. 32,33 These CXCR2 deficiency studies also indicated that CXCR2 expression by intimal macrophages was both an early and persistent feature of atherosclerosis, suggesting that CXCR2 expression on the lesion macrophage was acquired sometime during their transformation into macrophage foam cells. CXCR2 expression can be upregulated in vitro as monocytes make contact with endothelial cells, 34 thereby modulating monocyte-endothelial cell adhesion.…”

Association Between Plasma Levels of Monocyte Chemoattractant Protein-1 and Long-Term Clinical Outcomes in Patients With Acute Coronary Syndromes

“…21 Expression of both MCP-1 and its monocyte receptor are upregulated in hypercholesterolemia, a finding that appears to be mediated directly by lipids and lipid metabolites. 22 LDL receptordeficient mice that undergo targeted deletion of the MCP-1 gene are resistant to the effects of a cholesterol-rich diet and have markedly less atherosclerosis than similar mice who do not undergo deletion of the MCP-1 gene. 7 Similarly, mice lacking the receptor for MCP-1 (CCR2) are resistant to the development of atherosclerosis.…”