Manipulation of Leucocytic NADPH Oxidase Maturation May Drive Macrophage Differentiation and Affect Atherogenesis

Abstract

Abstract Atherosclerosis is a process of arterial intima thickening caused by lipid deposition as a consequence of insufficient efferocytosis of apoptotic cells by M2 macrophages and excessive inflammatory cytokine secretion from M1 macrophages. NADPH oxidase 2 (NOX2) is recognized as a major source of ROS for enhancing macrophage efferocytosis and functional polarization. We previously found that human macrophages contain significant amount of endoplasmic reticulum (ER)-retained gp91 phox, a major component of NOX2, which may hinder the formation of functional NOX2. To address the role of macrophage NOX2 in atherosclerosis, we established a mouse model bearing Apoe −/−and the CYBBpoint mutation (C1024T), which leads to ER-retained gp91 phoxin immune cells. We also developed a method for targeted delivery of a SERCA inhibitor with poly (lacticcoglycolic acid) (PLGA) nanoparticles (NPs), which may promote the glycosylation and maturation of ER-retained gp91 phox. We first found that oxLDL-administrated M1 macrophages expressed increased M2 marker CD163 and increased efferocytotic ability after being treated with NPs. We also found that there was an increased glycosylation of gp91 phoxin those macrophages from human and mice with CYBBpoint mutation (C1024T) after the treatment of NPs. Macrophage ATP-binding cassette transporters, which could decrease cholesterol overloading in macrophages, were upregulated in macrophages after macrophages were treated with NPs. Our results demonstrated that NPs not only can recover the maturation of ER-retained gp91 phoxin macrophages but also may facilitate the differentiation of M1 to M2-like macrophages with enhanced efferocytotic activity and cholesterol efflux.