Chemokine Receptors and Atherosclerosis

Chemokines, Chemokine Receptors and Atherosclerosis A. CCL2 and CCR2... 

Table 6.7 Chemokine receptors and their ligands involved in atherosclerosis.

Chemokines have been shown to be associated with a number of autoinflammatory diseases including multiple sclerosis, rheumatoid arthritis, atherosclerosis, dermatitis, and organ transplant rejection. Evidence, reviewed below, is mounting that chemokines may play a major role in the pathophysiology of these diseases and thus chemokine receptor antagonists could prove to be useful therapeutics in treating these and other proinflammatory diseases. 

The basic biology of chemokines and their receptors is well covered in Chapters 2 and 3 of this book, and we will focus hereafter upon the roles of individual chemokines and receptors in atherosclerosis. The largest amount of data on the roles of chemokines in cardiovascular disease (C VD) has been obtained from in vitro studies and murine models, which will be discussed in detail. In man, genetic polymorphisms in chemokine and chemokine-receptor genes have pointed to an important role for specific chemokines in various atherosclerotic diseases including coronary artery disease and carotid artery occlusive disease. For properties see Table 1. 

McDermott DH, Halcox JP, Schenke WH, et al. Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circ Res 2001 89(5) 401—407. 

Veillard NR, Steffens S, Pelli G, et al. Differential influence of chemokine receptors CCR2 and CXCR3 in development of atherosclerosis in vivo. Circulation 2005 112(6) 870-878. 

The chemotaxis of mononuclear leukocytes and the migration, growth, and activation of the multiple cell types within atherosclerotic lesions are critical for the chronic inflammatory and fibroproliferative response in atherosclerosis (Ml). Chemokine-mediated attraction of leukocytes to tissues has been shown in atherosclerotic lesions (G8). Studies using knockout and transgenic murine models indicated that chemokine receptor/ligand interactions are crucial in the development of atherosclerosis (P6). Moreover, chemokines may also interfere with smooth muscle cell migration and growth, and platelet activation and other well-defined features of the atherosclerotic process (A2). 

P6. Peters, W., and Charo, I. F., Involvement of chemokine receptor 2 and its ligand, monocyte chemoattractant protein-1, in the development of atherosclerosis Lessons from knockout mice. Curr. Opin. Lipidol. 12, 175—180 (2001). 

Based on their broad range of fimctions, the chemokines are easily deduced to be important players in diseases characterized by inflammation and cell infiltration, such as asthma, atherosclerosis, rheumatoid arthritis, multiple sclerosis, colitis, Crohn s disease, experimental autoimmune encephalomyelitis (EAE), and psoriasis, among others (8). Finally, CXCR4 and CCR5 are the two main coreceptors for HIV-1 infection (9)., some chemokine receptors also participate in tumor metastasis (7) and transplant rejection (10). 

Chemokines are key players in inflammatory diseases such as rheumatoid arthritis, atherosclerosis, and asthma (reviewed in Koelink et al., 2012) and in the evolution of and metastatic spread of tumors (reviewed in Balkwill, 2012). The strategy of adding chemokine receptor agonists to vaccine adjuvants in order to boost immune reactions is being explored (Bobanga, Petrosiute, Huang, 2013), and the chemokine receptors that are used by HIV as entry coreceptors represent important targets for antiviral prevention and therapy (Kuhmann Hartley, 2008). 

Poupel, L., Boissonnas, A., Hermand, P., Dorgham, K., Guyon, E., Auvynet, C., et al. (2013). Pharmacological inhibition of the chemokine receptor, CX3CR1, reduces atherosclerosis in mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 33, 2297—2305. 

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