Figure 1.

Stage-dependent role of neutrophils in atherosclerosis. During the early stage of atherosclerosis, upregulation of E-selectin, P-selectin, and ICAM-1 induces neutrophil recruitment. Platelet-derived CCL5 activates neutrophils to release cathepsin G, leading to the firm adhesion to and accumulation of neutrophils in the endothelium. ROS and proteases secreted by neutrophils activate and dysregulate the endothelial cell layer and degrade the underlying extracellular matrix, resulting in monocyte infiltration and LDL extravasation. Neutrophils secrete MPO that mediates LDL oxidation and promotes foam cell formation. Cathelicidin- and α-defensin-derived neutrophils activate macrophages towards pro-inflammatory state, while NETs stimulate macrophage to release IL-6 and IL-1β that promote Th17 differentiation followed by the amplification of neutrophil recruitment. At the late stage of atherosclerosis, activated VSMCs induce neutrophil chemotaxis and release CCL7 to stimulate NETs. Histone H4-derived from NETs induces VSMC lysis and the secretion of proteases by neutrophils degrades collagen and lyses VSMCs, leading to the plaque instability. Neutrophils contribute to plaque erosion through NET release as well as colocalization with TLR2 of endothelial cells to induce endothelial cell stress and apoptosis.