Rationale: A crucial step in atherogenesis is the infiltration of the subendothelial space of large arteries by monocytes where they differentiate into macrophages and transform into lipid-loaded foam cells. Macrophages are heterogeneous cells that adapt their response to environmental cytokines. Th1 cytokines promote monocyte differentiation into M1 macrophages, whereas Th2 cytokines trigger an "alternative" M2 phenotype. Objective: We previously reported the presence of CD68؉ mannose receptor (MR) ؉ M2 macrophages in human atherosclerotic plaques. However, the function of these plaque CD68 ؉ MR؉ macrophages is still unknown. Methods and Results: Histological analysis revealed that CD68؉ MR ؉ macrophages locate far from the lipid core of the plaque and contain smaller lipid droplets compared to CD68؉ MR ؊ macrophages. Interleukin (IL)-4 -polarized CD68؉ MR ؉ macrophages display a reduced capacity to handle and efflux cellular cholesterol because of low expression levels of the nuclear receptor liver x receptor (LXR)␣ and its target genes, ABCA1 and apolipoprotein E, attributable to the high 15-lipoxygenase activity in CD68؉ MR ؉ macrophages. By contrast, CD68 ؉ MR؉ macrophages highly express opsonins and receptors involved in phagocytosis, resulting in high phagocytic activity. In M2 macrophages, peroxisome proliferator-activated receptor (PPAR)␥ activation enhances the phagocytic but not the cholesterol trafficking pathways. Key Words: atherosclerosis Ⅲ macrophages Ⅲ nuclear receptors Ⅲ cholesterol A crucial step in atherogenesis is the infiltration of monocytes within the subendothelial space of large arteries and their differentiation into macrophages. In early plaques, recruited macrophages play reparatory roles via the phagocytosis of oxidized lipids and apoptotic cells. However, during atherosclerosis progression, macrophages contribute to foam cell formation, lesion growth, plaque rupture and thrombosis by secreting immune-inflammatory factors, growth factors, proteolytic enzymes and tissue factor. 1 One of the most important functions of macrophages in the context of atherosclerosis is the handling of lipids, especially cholesterol. The maintenance of macrophage cholesterol homeostasis is of critical importance in the pathogenesis of atherosclerosis, because an imbalance between cholesterol influx and efflux leads to an excessive accumulation of cholesterol in macrophages and their transformation into foam cells. 2,3 Macrophage scavenger receptors, including scavenger receptor (SR)-A, CD36, and lectin-like oxidized low-density lipoprotein (LDL) receptor (LOX)-1, mediate the uptake of modified LDL lipoproteins, including oxidized LDL. Within the macrophages, modified LDL-derived cholesteryl esters are hydrolyzed in lysosomes by the lysosomal acid lipase (LAL). The released unesterified cholesterol traffics to and integrates in the plasma membrane. The excess Original received October 1, 2010; revision received February 15, 2011; accepted February 17, 2011. In January 2011, the average time from submissi...

Aims/hypothesis Human adipose tissue macrophages (ATMs) display an alternatively activated (M2) phenotype, but are still able to produce excessive inflammatory mediators. However, the processes driving this particular ATM phenotype are not understood. Genome-wide association studies associated the CDKN2A locus, encoding the tumour suppressor p16 INK4A , with the development of type 2 diabetes. In the present study, p16INK4A levels in human ATMs and the role of p16 INK4A in acquiring the ATM phenotype were assessed. Methods Gene expression of p16 INK4A in ATMs was analysed and compared with that in monocyte-derived macrophages (MDMs) from obese patients or with macrophages from human atherosclerotic plaques (AMs). Additionally, p16INK4A levels were studied during macrophage differentiation and polarisation of monocytes isolated from healthy donors.