Inflammatory Chemokines in Atherosclerosis

Abstract

Atherosclerosis is a long-term, chronic inflammatory disease of the vessel wall leading to the formation of occlusive or rupture-prone lesions in large arteries. Complications of atherosclerosis can become severe and lead to cardiovascular diseases (CVD) with lethal consequences. During the last three decades, chemokines and their receptors earned great attention in the research of atherosclerosis as they play a key role in development and progression of atherosclerotic lesions. They orchestrate activation, recruitment, and infiltration of immune cells and subsequent phenotypic changes, e.g., increased uptake of oxidized low-density lipoprotein (oxLDL) by macrophages, promoting the development of foam cells, a key feature developing plaques. In addition, chemokines and their receptors maintain homing of adaptive immune cells but also drive pro-atherosclerotic leukocyte responses. Recently, specific targeting, e.g., by applying cell specific knock out models have shed new light on their functions in chronic vascular inflammation. This article reviews recent findings on the role of immunomodulatory chemokines in the development of atherosclerosis and their potential for targeting.

Keywords: atherosclerosis; cardiovascular disease; chemokine receptors; chemokines; inflammation; mouse models.

Figure 1

Schematic and simplified overview of the effects that chemokine-chemokine receptor axis have on leukocyte recruitment. Various chemokines and chemokine receptors are visualized that play a role in leukocyte recruitment. Activated endothelial cells secrete a wide variety of chemokines that attract leukocytes like monocytes and neutrophils towards the vessel wall in a process called chemotaxis, followed by tethering, rolling and transmigration. Furthermore, activated macrophages secrete chemokines that stimulate this leukocyte recruitment process and it has been shown that chemokine receptors influence endothelial permeability, which is an important aspect for leukocyte transmigration (Created with Biorender.com).

Figure 2

Schematic and simplified overview of the effects that chemokine-chemokine receptor axis have on atherosclerotic processes inside the vessel wall. In the vessel wall, various chemokines and chemokine receptors play an important role in cellular processes. Secreted chemokines contribute to the leukopedesis and stimulates foam cell formation. Furthermore, chemokines contribute to macrophage polarization and the formation of neutrophil extracellular traps (NETs). Besides effects on myeloid cells, also lymphocytes are affected as dendritic cell mediated T cell activation is stimulated by chemokines. Finally, chemokine and chemokine receptors contribute to smooth muscle cell (SMC) proliferation, lipid uptake and release of matrix metalloproteases. (Created with Biorender.com).