New Insights into the Role of Inflammation in the Pathogenesis of Atherosclerosis

Meng-Yu Wu, Chia-Jung Li, Ming-Feng Hou, Pei-Yi Chu, Meng-Yu Wu, Chia-Jung Li, Ming-Feng Hou, Pei-Yi Chu

Abstract

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids, smooth muscle cell proliferation, cell apoptosis, necrosis, fibrosis, and local inflammation. Immune and inflammatory responses have significant effects on every phase of atherosclerosis, and increasing evidence shows that immunity plays a more important role in atherosclerosis by tightly regulating its progression. Therefore, understanding the relationship between immune responses and the atherosclerotic microenvironment is extremely important. This article reviews existing knowledge regarding the pathogenesis of immune responses in the atherosclerotic microenvironment, and the immune mechanisms involved in atherosclerosis formation and activation.

Keywords: atherosclerosis; atherosclerotic immunity; atherosclerotic microenvironment; macrophage; oxidative stress.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Small low-density lipoproteins (LDLs) penetrate the endothelial barrier and bind to proteoglycans via apolipoprotein B100 to retain in the subendothelial space. LDL is oxidized (ox-LDL) and induces several pro-inflammatory conditions via lectin-like oxidized LDL receptor-1 (LOX-1). The upregulation of intercellular adhesion molecule-1 (ICAM-1) and vascular-cell adhesion molecule-1 (VCAM-1) by ox-LDL increase monocyte and inflammatory cell adhesion on the endothelium. Ox-LDL particles stimulate endothelial cells and smooth muscle cells (SMCs) to secrete monocyte chemotactic protein-1 (MCP-1) and monocyte colony stimulating factor (M-CSF), with both factors inducing monocyte recruitment. Ox-LDL promotes an increased in reactive oxygen species (ROS) and inhibits nitric oxide production. Monocytes differentiate into macrophages and express scavenger receptors (SRs), cluster of differentiation 36 (CD36), LOX-1, and Toll-like receptors (TLRs). Ox-LDL–CD36 interaction induces monocyte differentiation, macrophage activation, and macrophage retention, and macrophage SRs increase ox-LDL uptake and foam-cell formation. The retention of ox-LDL leads to foam cell apoptosis and inflammatory progression. Ox-LDLs also increase the expression of growth factors, including platelet-derived growth factor (PDGF) for migration and basic fibroblast growth factor (bFGF) for proliferation, on SMCs. SMC proliferation contributes to the thickening of atherosclerotic plaques and formation of a necrotic core. The ox-LDL–CD36 interaction in resting platelets causes platelet aggregation and activation, with activated platelets expressing LOX-1 to mediate adhesion to endothelial cells and enhance endothelin-1 release. The endothelial function is impaired along with decreasing nitric oxide production and increasing prostaglandin synthesis.
Figure 2
Figure 2
Hyperlipidemic status and other conditions can induce the accumulation of advanced glycation end products (AGEs), leading to increase reactive oxygen species (ROS) and retention of oxidized low-density lipoprotein (ox-LDL). Oxidative stress causes endothelial dysfunction and impairs the release of nitric oxide (NO) and endothelin-1 (ET-1). In atherosclerotic lesions, elevated tissue levels of ET-1 bind to ETB receptors on endothelial cells and cause expression of endothelial cell adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular-cell-adhesion molecule-1 (VCAM-1). ET-1 promotes monocyte migration and activation by monocyte chemoattractant protein-1 (MCP-1), which is released from activated macrophages and endothelial cells. ET-1 also activates vascular smooth muscle cells (VSMCs) via ETA receptors to promote SMC proliferation. Oxidative stress also causes lower tissue levels of BH4 and induces the uncoupling of endothelial nitric oxide synthase (eNOS) and superoxide.
Figure 3
Figure 3
The role of inflammatory cells in atherosclerotic lesion.

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