The Ins and Outs of Myeloid Cells in Atherosclerosis

Abstract

Atherosclerosis is a chronic inflammation of the arterial vessel wall that arises from an imbalanced lipid metabolism. A growing body of literature describes leukocyte recruitment as a critical step in the initiation and progression of lesion development. By contrast, the role of leukocytes during plaque regression has been described in less detail. Leukocyte egress might be an important step to resolving chronic inflammation and therefore it may be a promising target for limiting advanced lesion development. This review aims to summarize our current knowledge of leukocyte recruitment to the arterial vessel wall. We will discuss mechanisms of leukocyte egress from the lesion site, as well as potential therapeutic strategies to promote atherosclerotic regression.

Keywords: Atherosclerosis; Chemokines; Inflammation; Monocytes.

Fig. 1

Myeloid cell recruitment to atherosclerotic lesions. Imbalanced myeloid cell recruitment during lesion progression triggers chronic inflammation. Under inflammatory conditions, platelets secrete chemokine ligand 5 (CCL5), thus activating neutrophils to release cationic granular proteins or inducing neutrophil extracellular trap formation. Chemotactic, neutrophil-derived granule proteins (e.g., cathelicidin and cathepsin G) bind to endothelial cells and mediate monocyte adhesion. In addition, monocytes start to roll along adhesion molecules, which are presented on the endothelium and finally adhere via E-selectin-, P-selectin-, intercellular cell adhesion molecule-1-, or vascular cell adhesion molecule-1-mediated cell arrest. The endothelial cell adhesion molecule and chemokine expression as well as myeloid cell recruitment are regulated by circadian rhythmicity. Adherent monocytes try to find their way to transmigration through the endothelium into the intima, where monocyte-derived macrophages phagocyte oxLDL. NET, neutrophil extracellular traps.

Fig. 2

Myeloid cell egress. Macrophages, derived from transmigrated monocytes, release matrix metalloproteinases (MMP) which degrade extracellular matrix components and integrins on macrophages. Soluble integrins-β₂ block adhesion molecules, which enable macrophages to leave atherosclerotic plaques through the media to adventitial lymphatic vessels. Macrophage liver X receptor (LXR) activation increases chemokine receptor 7 (CCR7) expression and fosters the reverse transmigration of macrophages. Neutrophil reentry into the circulation is caused by macrophage interaction via redox-regulated Src family kinase signaling. To reverse transmigration through endothelial cells, neutrophils release neutrophil elastase (NE) in response to leukotriene B₄ (LTB₄). NE cleaves endothelial cell junction adhesion molecule-C (JAM-C). Altered JAM-C distribution enables neutrophils to leave the lesion site and reenter into circulation. Tissue-experienced neutrophils express high levels of intercellular adhesion molecule-1 (ICAM-1) and low levels of chemokine receptor CXCR1 on their cell surface.