Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARgamma and LXRalpha pathways. Circ Res. 2011;108 (8):985–95. This group (also reference 76) was the first

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 CD68MR macrophages is still unknown. Methods and Results: Histological analysis revealed that CD68MR macrophages locate far from the lipid core of the plaque and contain smaller lipid droplets compared to CD68MR macrophages. Interleukin (IL)-4–polarized CD68MR 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 CD68MR macrophages. By contrast, CD68MR 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. Conclusions: These data identify a distinct macrophage subpopulation with a low susceptibility to becom