Regulation of Atherogenesis by Chemokines and Chemokine Receptors
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REVIEW
Regulation of Atherogenesis by Chemokines and Chemokine Receptors Wuzhou Wan • Philip M. Murphy
Received: 4 June 2012 / Accepted: 18 November 2012 / Published online: 7 December 2012 Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2012
Abstract Atherosclerosis is a chronic inflammatory and metabolic disorder affecting large- and medium-sized arteries, and the leading cause of mortality worldwide. The pathogenesis of atherosclerosis involves accumulation of lipids and leukocytes in the intima of blood vessel walls creating plaque. How leukocytes accumulate in plaque remains poorly understood; however, chemokines acting at specific G protein-coupled receptors appear to be important. Studies using knockout mice suggest that chemokine receptor signaling may either promote or inhibit atherogenesis, depending on the receptor. These proof of concept studies have spurred efforts to develop drugs targeting the chemokine system in atherosclerosis, and several have shown beneficial effects in animal models. This study will review key discoveries in basic and translational research in this area. Keywords Atherosclerosis Cardiology Immunology Inflammation Antagonist
Introduction Atherosclerosis is the pathologic process underlying most strokes and heart attacks, which together are now the leading cause of death worldwide (Roger et al. 2012). Risk factors for atherosclerosis include age, gender, a high ratio of lowdensity lipoprotein (LDL) to high-density lipoprotein (HDL)
W. Wan P. M. Murphy (&) Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bldg 10, Rm 11N113, Bethesda, MD 20892, USA e-mail: [email protected]
in the blood, hypertension, diabetes, obesity, smoking and inheritance (Berger et al. 2010). It is generally accepted that atherosclerosis is a chronic metabolic and inflammatory disease (Hansson 2005). The pathologic hallmark is the atherosclerotic plaque, composed of lipids, collagen, platelets, fibroblasts, smooth muscle cells (SMCs) and leukocytes. Rupture of unstable plaques may result in thrombosis and ischemia in surrounding tissues (Weber et al. 2008; Weber and Noels 2011). Both innate and adaptive immunity appear to be involved in the development of plaque (Packard et al. 2009). Innate immune cells, including macrophages, neutrophils, mast cells and platelets, accumulate early and express reactive oxygen species (ROS), proteinases, lipid mediators and various cytokines, leading to SMC proliferation, angiogenesis and additional inflammatory cell activation. Adaptive immune cells, including T and B lymphocytes, accumulate later and may accelerate disease progression through complex and poorly understood mechanisms (Galkina and Ley 2009; Weber et al. 2008). In particular, in mouse models, the B1 subset of B cells is atheroprotective, whereas the B2 subset is pro-atherogenic; Th1 cells are pro-atherogenic, and regulatory T cells (Tregs) are atheroprotective, whereas the roles
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