The role of chemokines in atherosclerosis: recent evidence from experimental models and population genetics Christina A. Bursill a,b , Keith M. Channon a and David R. Greaves b Purpose of review Atherosclerosis is an inflammatory disease process. This review discusses the recent genetic evidence from animal models and human populations that highlight the importance of chemokines in atherosclerosis. Recent findings CC-chemokine/CC-chemokine receptors (CCR), including CCR2/ MCP-1 (monocyte chemoattractant protein-1) and CCR5/RANTES (regulated on activation, normal T-cell expressed and secreted), have been shown in animal knockout and transgenic studies to have significant effects on atherosclerotic lesion size and macrophage recruitment. More recently fractalkine (CX 3 C1) and its receptor (CX 3 CR1) have emerged as another important pathway in atherosclerosis. For example, fractalkine is present in human atherosclerotic lesions and is able to stimulate platelet activation and adhesion. CX 3 CR1 is expressed on human aortic smooth muscle cells and CX 3 CR1/apolipoprotein E double knockout mice have significantly reduced atherosclerotic lesion size and macrophage recruitment. Human population genetic studies have tried to assess the importance of chemokines in human atherosclerosis. Currently, there is conflicting evidence regarding an association between polymorphisms in CCR2/ MCP-1 and CCR5/RANTES and coronary artery disease. There is evidence, however, for an association between the fractalkine receptor polymorphism (CX 3 CR1-I249) and coronary artery disease in both human population and function studies. Summary Recent transgenic and gene knockout studies in murine models of atherosclerosis have highlighted the importance of chemokines and their receptors in atherosclerosis. Genetic evidence for a role of chemokines and their receptors in human population studies remains under investigation. Identifying chemokine polymorphisms could help to determine pathways that are important in atherosclerosis disease pathology and that may suggest novel therapeutic targets. Keywords CC-chemokine, coronary artery disease, fractalkine, inflammation, polymorphism Curr Opin Lipidol 15:145–149. # 2004 Lippincott Williams & Wilkins. a Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, and b Sir William Dunn School of Pathology, University of Oxford, Oxford, UK Correspondence to Dr David R. Greaves, Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK Tel: +44 1865 285519; fax: +44 1865 275515; e-mail: David.Greaves@pathology.oxford.ac.uk Current Opinion in Lipidology 2004, 15:145–149 Abbreviations ApoE apolipoprotein E CAD coronary artery disease CCR CC-chemokine receptor CX 3 CR1 CX 3 C1 (fractalkine) receptor MCP monocyte chemoattractant protein MI myocardial infarction SMC smooth muscle cell RANTES regulated on activation, normal T-cell expressed and secreted # 2004 Lippincott Williams & Wilkins 0957-9672 Introduction Increasing evidence suggests that atherosclerosis is an inflammatory disease in which chemokines play an important role. Chemokines are chemoattractant cyto- kines that come from a large family of approximately 50 currently identified ligands and 20 different receptors [1]. They are divided into four different subfamilies (C, CC, CXC and CX 3 C), based on the number and structural arrangement of conserved cysteine residues within their polypeptide sequence. Their main function is to direct the migration of specific leucocytes to sites of inflammation or infection. Chemokines therefore play important roles in the pathogenesis of many inflamma- tory diseases, such as rheumatoid arthritis, asthma, multiple sclerosis and transplant rejection. Atherosclero- sis involves the activation of chemokines on the surface of the vascular endothelium and the recruitment of inflammatory cells (monocytes/macrophages) into the vessel wall [2]. Within the subendothelial space, macro- phages rapidly accumulate lipid to form foam cells and these can trigger further inflammatory responses invol- ving an increase in reactive oxygen species, growth factors, and proinflammatory cytokines and chemokines. Atherosclerosis is therefore an inflammatory disease in which chemokines play an important role [3]. The present review discusses recent genetic evidence in both animal models and human populations regarding the importance of chemokines in atherosclerosis. Animal studies Animal knockout, transgenic and gene therapy studies have highlighted the importance of chemokines, parti- cularly the CC-chemokines and fractalkine, in athero- sclerosis. CC-chemokines Several animal studies have revealed a role for CC- chemokines in atherosclerosis. Boring et al. [4] found that DOI: 10.1097/01.mol.0000124526.75650.13 145