Cytokines in atherosclerosis: Key players in all stages of disease and promising therapeutic targets

Abstract

Atherosclerosis, a chronic inflammatory disorder of the arteries, is responsible for most deaths in westernized societies with numbers increasing at a marked rate in developing countries. The disease is initiated by the activation of the endothelium by various risk factors leading to chemokine-mediated recruitment of immune cells. The uptake of modified lipoproteins by macrophages along with defective cholesterol efflux gives rise to foam cells associated with the fatty streak in the early phase of the disease. As the disease progresses, complex fibrotic plaques are produced as a result of lysis of foam cells, migration and proliferation of vascular smooth muscle cells and continued inflammatory response. Such plaques are stabilized by the extracellular matrix produced by smooth muscle cells and destabilized by matrix metalloproteinase from macrophages. Rupture of unstable plaques and subsequent thrombosis leads to clinical complications such as myocardial infarction. Cytokines are involved in all stages of atherosclerosis and have a profound influence on the pathogenesis of this disease. This review will describe our current understanding of the roles of different cytokines in atherosclerosis together with therapeutic approaches aimed at manipulating their actions.

Keywords: Atherosclerosis; Chemokines; Cytokines; Inflammation; Therapeutic avenues.

Fig. 1

Pathogenesis of atherosclerosis. The disease is initiated by the activation of the endothelium/endothelial cell (EC) dysfunction by accumulation of LDL, which subsequently gets modified (e.g. oxidized), together with other atherogenic factors. The activated ECs secrete a range of chemokines and increase the expression of adhesion proteins on their cell surface. This results in the recruitment and infiltration of immune cells such as monocytes. The monocytes differentiate into macrophages, which is accompanied by increased expression of pattern recognition receptors on their surface, which participate in the promotion of inflammation and uptake of modified LDL, leading to the formation of lipid laden foam cells. Continued accumulation of modified LDL together with disturbed cellular lipid homeostasis causes apoptosis/necrosis of foam cells resulting in lipid deposition (necrotic core) and amplification of the inflammatory response. Smooth muscle cells (SMCs) migrate from the media to the intima where they proliferate, uptake modified lipoproteins and secrete extracellular matrix (ECM) proteins that stabilizes the plaques (fibrous cap). Continued inflammation orchestrated by cytokines destabilizes such plaques via decreased production of ECM proteins (reduced synthesis together with apoptosis/necrosis of SMCs/SMC-derived foam cells), increased production/activities of ECM degrading matrix metalloproteinases (MMPs) and reduced expression/activities of inhibitors of these enzymes. Plaque rupture leads to platelet aggregation, coagulation and thrombus formation that ultimately results in the clinical complications associated with this disease. Cytokines affect all the different stages in the pathogenesis of atherosclerosis (see text for details). Abbreviations: ECM, extracellular matrix; LDL, low-density lipoprotein; MMP, matrix metalloproteinase; SMC, Smooth muscle cells; TIMP, tissue inhibitor of metalloproteinase.