Macrophage Subsets in Human Atherosclerosis
Authors: Aloke V. Finn, Omar Saeed, Renu Virmani
Journal: Circulation Research (2012)

Macrophages are the major inflammatory cells involved in the progression of atherosclerosis.Microenvironment directs these cells into morphologically and functionally distinct phenotypes.It has been classically thought that macrophages exist in two distinct subtypes: (1) "classically" activated (M1) macrophages, which are induced by Th1 cytokines such as interferon-␥ and lipopolysaccharide and produce proinflammatory cytokines and (2) alternative M2 cells, which are stimulated by Th2 cytokines such as IL-4 or IL-13 and produce anti-inflammatory cytokines such as IL-10.Evidence for the existence of M2 macrophages in human atherosclerosis recently was shown by Chinetti-Gbaguidi et al 1 using histological analysis of human atherosclerotic plaques to characterize a subpopulation of CD68 ϩ cells that were positive for the mannose receptor (MR), a surface marker for M2 macrophages.These cells contained minimal amounts of lipid by oil red O stain.To support their contention that these cells are IL-4 -induced M2 macrophages, the authors show higher levels of IL-4 mRNA by laser capture microdissection in only four human plaques from CD68 ϩ MR ϩ -positive versus CD68 ϩ MR Ϫ areas.It must be stated that a great deal of their conclusions rely on this finding when, in fact, in our opinion, mRNA analysis alone without any supportive immunohistochemical or protein analysis seems inadequate to draw this sweeping conclusion.The authors go on to explore the lipid handling properties of CD68 ϩ MR ϩ macrophages and report that intraplaque levels of ABCA1, apolipoprotein E, and LXR␣ mRNA are reduced in regions containing CD68 ϩ MR ϩ macrophages in comparison to CD68 ϩ MR Ϫ areas.In vitro studies of IL-4 differentiated macrophages (M2) loaded with acetylated low-density lipoprotein showed reduced apolipoprotein A1 and HDL 3 -mediated efflux of [ 3 H]-cholesterol.In summary, the authors concluded that the subpopulation of CD68 ϩ MR ϩ macrophages in the atherosclerotic plaque have limited cholesterol efflux capacity because of an inactivated LXR␣ pathway and mainly function as phagocytes.Although we commend Chinetti-Gbaguidi et al for their series of eloquent ex vivo and in vitro analyses to define the characteristics of CD68 ϩ MR ϩ macrophages, we must point out the discrepant findings with our own investigations of CD68 ϩ MR ϩ macrophages in human atherosclerosis.We recently reported that these macrophages are found exclusively in areas of previous intraplaque hemorrhage and also express high levels of CD163 (hemoglobin[Hb]:haptoglobin receptor), produce antiinflammatory cytokines such as IL-10, and are devoid of lipids typical of foamy macrophages. 2In vitro studies demonstrated that the MR ϩ CD163 ϩ phenotype could only be reproduced by exposure of monocytes to Hb:haptoglobin complexes, likely formed on red cell hemolysis in response to the pro-oxidant environment of atherosclerosis.We termed these cells M(Hb).Consistent with previous reports, IL-4 upregulated MR expression but not CD163 in human monocytes, and IL-4 -induced macrophages were not as resistant to cholesterol loading as Hb:haptoglobin differentiated cells.Characteristics of a nonfoam