Novel mechanism of regulation of the 5-lipoxygenase/leukotriene B ₄ pathway by high-density lipoprotein in macrophages

Abstract

High-density lipoprotein (HDL) interacts with various cells, particularly macrophages, in functional cell-HDL interactions. Here, we found that HDL protein quality and lipid quality play critical roles in HDL functions. HDL fractions from healthy volunteers (HDL _Healthy) and patients with recurrent coronary atherosclerotic disease (HDL _CAD) were prepared. To analyse functional HDL-macrophage interactions, macrophages were co-incubated with each HDL, and lipid mediator production was assessed by liquid chromatography/mass spectrometry-based metabololipidomics. HDL _Healthy treatment attenuated the pro-inflammatory lipid mediator production, particularly that of leukotriene (LT) B ₄, and this treatment enhanced lipoxin (LX) B ₄ and resolvin (Rv) E2 production. HDL _Healthy treatment enhanced the proteasome-mediated degradation of the LTB ₄-producing enzyme 5-lipoxygenase (LO) in activated macrophages; however, HDL _CAD did not show these anti-inflammatory effects. HDL _Healthy was engulfed by macrophages via clathrin-mediated endocytosis, which was a critical step in 5-LO/LTB ₄ regulation. We also found that HDL _CAD showed higher levels of the LTB ₄-producing enzymes and thus promoted LTB ₄ production from HDL _CAD. In addition, LTB ₄ attenuated HDL endocytosis, HDL-mediated 5-LO degradation in macrophages, and HDL-derived augmentation of macrophage phagocytosis. These results indicated that local LTB ₄ produced de novo from HDL _CAD regulates HDL-macrophage functional interactions and plays critical roles in dysfunctional, inflammatory HDL characteristics.