Macrophage functions in atherosclerosis.

Abstract

Atherosclerosis is a chronic inflammatory disease of the arterial wall instigated by the excessive accumulation of lipoproteins; monocyte recruitment and their differentiation into macrophages in the subendothelial space. Repeated failure of innate immune responses to clear subintimal low-density lipoprotein (LDL), results in the deposition of lipid-laden macrophages or foam cells. Foam cells secrete proinflammatory mediators that facilitate lipoprotein retention and maintain vascular inflammation.1 Advancement of lesion is characterized by the apoptosis of these macrophages in the lipid core. Macrophage apoptosis plays a dual role in atherosclerosis. In early fatty streaks lesions, efferocytosis removes apoptotic cells and prevents lesion development, whereas in the advanced lesions, efferocytosis is not efficient to clear the apoptotic debri, leading to the formation of necrotic core which further enhances inflammation and atherogenesis.2 Accumulating indirect evidence suggests that the antiatherogenic role of high density lipoprotein (HDL) could at least in part, be due to its ability to stimulate cholesterol efflux from macrophages by ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1). Complementing this notion, recent studies by Westerterp et al3 show that macrophage deficiency of ABCA1/G1 enhances lipid accumulation in macrophages, atherosclerosis and lesion inflammation. These authors observed that macrophage foam cells in spleen facilitate monocytosis which is inhibited by ABCA1/G1 and high levels of HDL. Studies by Ramirez et al4 demonstrate that activation of liver X receptor (LXR) augments the transcription of microRNA 144 (miR144) and inhibition of miR144 in macrophages upregulates ABCA1 expression and cholesterol efflux. In vivo, supplementation of mice with miR144 suppresses ABCA1 expression in the liver and reduces plasma HDL levels. Silencing of miR144 …