Role of neutrophils in different stages of atherosclerosis

Abstract

Neutrophils constitute the first line of defense in human immunity and can be attracted to inflamed and infected sites by various chemokines. As essential players in immune processes, neutrophils theoretically play integral roles in the course of chronic inflammation-induced atherosclerosis. However, because neutrophils are rarely found in atherosclerotic lesions, their involvement in the pathophysiological progression of atherosclerosis has been largely underestimated or ignored. Recent research has revealed convincing evidence showing the presence of neutrophils in atherosclerotic lesions and has revealed neutrophil contributions to different atherosclerosis stages in mice and humans. This review describes the underlying mechanisms of neutrophils in different stages of atherosclerosis and highlights potential neutrophil-targeted therapeutic strategies relevant to atherosclerosis. An in-depth understanding of neutrophils' roles in atherosclerosis pathology will promote exploration of new methods for the prevention and treatment of atherogenesis and atherothrombosis.

Keywords: Atherosclerosis; granule protein; inflammation; neutrophil; neutrophil extracellular traps.

Figure 1.

Pathogenesis of atherosclerosis. a, The fatty streak phase of atherosclerosis begins with dysfunctional ECs and the retention of lipoproteins (LDL, VLDL, etc.) in the subendothelial space. b, Retained lipoproteins are modified (via oxidation, glycation, and enzymatic modification). c, The modified lipoproteins (mainly Ox-LDL), along with other atherogenic factors, promote activation of ECs and increase the expression of selectins, VCAM-1 and ICAM-1, leading to attachment of monocytes and other immune cells. d, These adherent monocytes and other immune cells migrate into the intimal space. e, Monocytes in the intimal space take up Ox-LDL and differentiate into foam cells. f and g, Foam cells and immune cells release a variety of cytokines, growth factors and ROS to stimulate SMCs migration and collagen deposition, leading to the development of an atheromatous plaque. h, In the advanced stage of atherosclerosis, upregulated MMPs destroy the fibrous caps of atherosclerotic plaques and the basement membranes of ECs, resulting in physical plaque disruption and thrombus formation.

Figure 2.

Neutrophils promote LDL vascular deposition and oxidation during the early stage of atherosclerosis. a, Defensin and LDL form stable complexes that bind to the endothelial surface. b, α-Defensins promote endothelial cathepsin expression and increase endothelial permeability to LDL. c, Activated neutrophils oxidize LDL to form Ox-LDL, releasing ROS, which induce endothelial damage. d, Ox-LDL induces NETs formation via TLR-PKC-IRAK-MAPK and NADPH oxidase activation. e, NETs release more ROS that in turn oxidize LDL to Ox-LDL.

Figure 3.

Neutrophils modulate the phenotypic differentiation of macrophages.