Cytokines: roles in atherosclerosis disease progression and potential therapeutic targets

Abstract

Atherosclerosis, the primary cause of cardiovascular disease (CVD), is a chronic inflammatory disorder in the walls of medium and large arteries. CVD is currently responsible for about one in three global deaths and this is expected to rise in the future due to an increase in the prevalence of obesity and diabetes. Current therapies for atherosclerosis mainly modulate lipid homeostasis and while successful at reducing the risk of a CVD-related death, they are associated with considerable residual risk and various side effects. There is, therefore, a need for alternative therapies aimed at regulating inflammation in order to reduce atherogenesis. This review will highlight the key role cytokines play during disease progression as well as potential therapeutic strategies to target them.

Keywords: atherosclerosis; cardiovascular disease; chemokines; cytokines; foam cells; inflammation; nanoparticles; neutralization.

Figure 1. Atherosclerosis disease progression and the role of key cytokines.

The accumulation of modified LDL within the intima of the artery triggers an inflammatory response in the nearby endothelial cells. The activated endothelial cells begin to express cell-adhesion molecules on their surface as well as secrete pro-inflammatory cytokines and chemokines which are able to recruit circulating monocytes to the affected region. Once in the intima, the monocytes differentiate into macrophages and begin to take up modified LDL and become foam cells. Overtime these foam cells can accumulate and form the initial atherosclerotic lesion. During atherosclerotic plaque maturation, foam cells start to undergo apoptosis or necrosis, which causes the formation of a necrotic core. To stabilise the necrotic core, smooth muscle cells migrate from media to intima and form a fibrous cap over the core by depositing extra cellular matrix. The chronic inflammatory response of atherosclerosis eventually causes the mature atherosclerotic plaque to become unstable and rupture, leading to a thrombotic reaction, which can cause a myocardial infarction or stroke depending on the location of plaque formation. ↑, increase; ↓, decrease; ?, unclear. CCL, Chemokine (C-C motif) ligand; CX₃CL1, Chemokine (C-X3-C motif) ligand; IFN, Interferon; IL, Interleukin; LDL, low-density lipoprotein; M-CSF, Macrophage colony stimulating factor; TGF, Transforming growth factor; TNF, Tumour necrosis factor.