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. 2021 Jun 7;12:682853. doi: 10.3389/fimmu.2021.682853

Figure 1.

Figure 1

Macrophage lipid metabolism disorder and thrombosis. Macrophages phagocytose accumulated LDL and modified LDL (such as oxLDL) through multiple cell membrane scavenger receptors such as LOX1, SR-A and CD36. In the lysosome, cholesterol ester (CE) in LDL particles is degraded to free cholesterol (FC) and free fatty acids by lysosomal acid lipase (LAL). In the endoplasmic reticulum (ER), FC is re-esterified by acetyl-coenzyme A: cholesterol acetyltransferase 1 (ACAT1), which contributes to CE accumulation and lipid droplet formation. CE is hydrolyzed by neutral cholesterol ester hydrolase 1 (NCEH1) to release FC, and is further transported to the outside of the cell through cholesterol efflux transporters, ABCA1, ABCG1 and SR-B1, thereby maintaining cholesterol metabolism homeostasis. Under pathological conditions (such as AS), excessive accumulation of FC induces the formation of cholesterol crystals in the lysosome, which activates the NLRP3 inflammasome, induces ER stress, and ultimately leads to the formation of foam cells. OxLDL can also activate the NF-κB signaling pathway through the CD36–TLR4/TLR6 trimer. Foam cells secrete macrophage chemotaxis retention factors (including netrin 1 and its receptor UNC5B, cadherins and semaphorin 3E), pro-inflammatory cytokines (such as IL-1, IL-6 and TNF) and chemokines (such as CCL2, CCL5 and CXCL1) amplify the inflammatory response. Over time, foam cells undergo apoptosis. When these apoptotic cells cannot be effectively cleared by macrophages in advanced disease (defective erythrocytosis), secondary necrosis will result. Further development will promote the formation of necrotic cores. At the same time, the living macrophages in the late plaque secrete cytokines, proteases and procoagulant thrombosis factors, as well as VSMCs death and protease degradation of the extracellular matrix. These effects weaken the stability of the fibrous cap (easy to rupture). The rupture leads to exposure of the thrombogenic substances in these lesions, which eventually causes platelet aggregation and thrombosis, resulting in MACE events. ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; CCL, C−C motif chemokine; CCR, C-C chemokine receptor; CD, cluster of differentiation; ER, endoplasmic reticulum; HDL, high-density lipoprotein; IL, Interleukin; LOX1, lectin-like oxidized LDL receptor 1; APOA1, lipid-poor apolipoprotein A1; NF-κB, nuclear factor kappa B; NLRP3, NOD-like receptor family pyrin domain containing 3; oxLDL, oxidized low-density lipoprotein; SRA, scavenger receptor class A; TLR, Toll-like receptor; SR-B1, scavenger receptor class B type 1.