Fig. 1.

Role of monocytes and neutrophils in atherosclerosis. a Lipoproteins enter the intima, bind to proteoglycans, accumulate, become modified and activate the endothelium. b Platelets deposit C–C motif chemokine ligand 5 (CCL5) on the endothelium, promoting neutrophil recruitment to the vessel wall. Activated neutrophils secrete granule proteins such as myeloperoxidase, azurocidin, and proteinase-3 that will enhance endothelial activation and dysfunction by inducing adhesion molecule expression, permeability changes and limiting the bioavailability of nitric oxide. Moreover, granule proteins secreted or deposited on the endothelium induce adhesion and recruitment of inflammatory monocytes, but can also modify chemokines, enhancing their ability to attract monocytes. c Activated endothelial cells release chemokines, such as MCP-1, that attract circulating monocytes. Monocytes bind to P and E selectin on endothelial cells, roll and finally come to arrest by adherence of their adhesion molecules (VLA-4, LFA-1) to VCAM-1 and ICAM1 on the endothelium. Platelets promote monocyte-endothelial interactions by expression of P-selectin, but can also form monocyte-platelet aggregates that further promote recruitment. Eventually, monocytes enter the intima through trans-endothelial diapedesis. d Infiltrated monocytes differentiate to macrophages, involving M-CSF, after which they polarize into various macrophage subsets (Ml, M2, M4 or MOX) that exert numerous effects and can become foams cells. Subset functions reviewed in Butcher et al. e Plaque neutrophils trap LDL in the vessel wall by secretion of α-defensin that binds LDL. f Neutrophils promote Ml polarization of macrophages. g Neutrophil-derived MMPs and MPO-dependent oxidative stress induces apoptosis of endothelial cells and degradation of basement membrane, leading to endothelial desquamation. h Neutrophil MMPs can also degrade ECM components affecting plaque stability. ECM extracellular matrix, MMP matrix metalloproteinase, MPO myeloperoxidase, LDL low-density lipoprotein, M-CSF macrophage colony stimulating factor, IFN interferon, TNF tumor necrosis factor, OxPAPC oxidation products of l-palmitoyl-2-arachidonoyl-sn-glycerol-3-phosphatidylcholine, EC endothelial cell, HOCI hypochlorous acid, PSGL-1 P-selectin glycoprotein ligand-1, VLA-4 very late antigen-4, VCAM-1 vascular cell adhesion molecule-1, LFA-1 leukocyte function-associated molecule 1, ICAM-1 intercellular adhesion molecule, SMC smooth muscle cell