Where the Action Is-Leukocyte Recruitment in Atherosclerosis

Abstract

Atherosclerosis is the leading cause of death worldwide and leukocyte recruitment is a key element of this phenomenon, thus allowing immune cells to enter the arterial wall. There, in concert with accumulating lipids, the invading leukocytes trigger a plethora of inflammatory responses which promote the influx of additional leukocytes and lead to the continued growth of atherosclerotic plaques. The recruitment process follows a precise scheme of tethering, rolling, firm arrest, crawling and transmigration and involves multiple cellular and subcellular players. This review aims to provide a comprehensive up-to-date insight into the process of leukocyte recruitment relevant to atherosclerosis, each from the perspective of endothelial cells, monocytes and macrophages, neutrophils, T lymphocytes and platelets. In addition, therapeutic options targeting leukocyte recruitment into atherosclerotic lesions-or potentially arising from the growing body of insights into its precise mechanisms-are highlighted.

Keywords: adhesion molecules; atherosclerosis; integrin; leukocyte recruitment; transendothelial migration; vascular inflammation.

Figure 1

Key factors in atherosclerosis-specific leukocyte recruitment. Leukocyte recruitment into atherosclerotic plaques is multifaceted and involves several players. Endothelial activation through disturbed flow patterns and oxidized lipoproteins, but possibly also via hyperglycemia or local sympathetic innervation, forms the basis for subsequent leukocyte-endothelial interactions. Of note, specific leukocyte populations respond differently to atherogenic triggers and use unique molecules and receptors to achieve leukocyte rolling, arrest, crawling and transmigration. Additionally, platelets strongly contribute to leukocyte recruitment by secondary leukocyte capture and activation of endothelial cells and leukocytes. AEG = advanced glycosylation end products; CCL, C-C motif chemokine ligand; CCR, C-C motif chemokine receptor; CD99, cluster of differentiation 99; cGMP, cyclic guanosine monophosphate; CXCL, C-X-C motif chemokine ligand; CX(3)CR, C-X(3)-C motif chemokine receptor; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; E-selectin, endothelial selectin; ICAM-1/2, intracellular adhesion molecule 1/2; Klf2, Krüppel-like factor 2; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; L-selectin, leukocyte selectin; Mac-1, macrophage receptor 1; NO, nitric oxide; (ox)LDL, (oxidized) lipoprotein; PECAM-1, platelet endothelial cell adhesion molecule 1; P-selectin, platelet selectin; PSGL-1, P-selectin glycoprotein ligand 1; ROS, reactive oxygen species; TLR, toll-like receptor; VCAM-1, vascular adhesion molecule 1; VE-cadherin, vascular endothelial cadherin; VLA-4, very late antigen 4; vWF, von Willebrand factor, YAP, yes-associated protein.

Figure 2

Pharmacological targets in atherosclerotic leukocyte recruitment. Simplified overview of approved (black) or potential (gray) targets in the process of leukocyte recruitment into atherosclerotic plaques. Substances with an incompletely clarified mechanism of action are marked with (?). CXCL2, C-X-C motif chemokine ligand 2; ICAM-1, intracellular adhesion molecule 1; ICAM-2, intracellular adhesion molecule 2; NO, nitric oxide; (ox)LDL, (oxidized) lipoprotein; PCSK9, proprotein convertase subtilisin/kexin type 9; VCAM-1, vascular adhesion molecule 1.