Liver X Receptor α-Dependent Iron Handling in M2 Macrophages

Abstract

In this issue of Circulation Research , Bories et al1 provide evidence of an interplay between cholesterol and iron metabolism, dominated by the nuclear receptor liver X receptor α (LXRα), in M2-like arterial macrophages. These data implicate LXRα as a primary regulator of an exquisitely controlled link between lipid and iron metabolism in macrophages and have important relevance for intraplaque hemorrhage associated with erythrophagocytosis in atherosclerotic lesions. Article, see p 1196 An understanding of the fate and diversity of the various monocyte/macrophage populations is needed to better comprehend the causes of atherosclerotic disease. The first evidence of macrophage diversity in human atherosclerotic plaques was reported in 2007 after identification of M1 and M2 polarized macrophages.2 Since then, it has become increasingly evident that macrophages display remarkable plasticity and can change their phenotype and function in response to environmental cues (Figure).3–6 Thus, functional, rather than genotypic and phenotypic, characterization of macrophage subsets has emerged in an attempt to better understand plaque morphology and composition. In earlier studies, it was shown that M1 and M2 polarized plaque macrophages are Oil red O–positive, suggesting that both subsets can participate in lipid uptake and become foam cells in vivo.7 Subsequently, Staels et al identified a population of M2 macrophages in human atherosclerotic plaques that express the mannose receptor (MR).8 Interestingly, this subset of M2 macrophages demonstrated reduced ability to handle lipids but remained highly competent for phagocytosis. The present study by Bories et al elegantly extends these findings in vivo by showing that iron preferentially accumulates in MR-positive (MR+) M2 polarized macrophages in human atherosclerotic plaques. Interestingly, the authors also observed that these cells were abundant in areas of neovascularization and speculated they could be relevant to intraplaque hemorrhage that may result from the delivery …