Liver X Receptor Activation Stimulates Iron Export in Human Alternative Macrophages

Abstract

Rationale: In atherosclerotic plaques, iron preferentially accumulates in macrophages where it can exert pro-oxidant activities. Objective: The objective of this study was, first, to better characterize the iron distribution and metabolism in macrophage subpopulations in human atherosclerotic plaques and, second, to determine whether iron homeostasis is under the control of nuclear receptors, such as the liver X receptors (LXRs). Methods and Results: Here we report that iron depots accumulate in human atherosclerotic plaque areas enriched in CD68 and mannose receptor (MR)-positive (CD68 + MR + ) alternative M2 macrophages. In vitro IL-4 polarization of human monocytes into M2 macrophages also resulted in a gene expression profile and phenotype favoring iron accumulation. However, M2 macrophages on iron exposure acquire a phenotype favoring iron release, through a strong increase in ferroportin expression, illustrated by a more avid oxidation of extracellular low-density lipoprotein by iron-loaded M2 macrophages. In line, in human atherosclerotic plaques, CD68 + MR + macrophages accumulate oxidized lipids, which activate LXRα and LXRβ, resulting in the induction of ABCA1, ABCG1, and apolipoprotein E expression. Moreover, in iron-loaded M2 macrophages, LXR activation induces nuclear factor erythroid 2-like 2 expression, thereby increasing ferroportin expression, which, together with a decrease of hepcidin mRNA levels, promotes iron export. Conclusions: These data identify a role for M2 macrophages in iron handling, a process regulated by LXR activation.

Liver X Receptor α-Dependent Iron Handling in M2 Macrophages

“…Thus, although the order in which iron loading versus M2 polarization was induced was different between the 3 studies, the iron handling capacity was similarly enhanced. For instance, Bories et al 1 show that M2 macrophages were able to increase their ferroportin levels and release more iron after iron loading, consistent with earlier studies using in vitro model systems. 17,18 Interestingly, in contrast to Mhem and M(Hb) cells, the newly identified Cxcl4-induced M4 macrophage subset expresses low amounts of CD163.…”

“…Furthermore, as speculated by the authors, a change in the ratio of MR + CD163 + and MR + CD163 − may occur during plaque progression as a result of higher or recurrent exposure to senescent erythrocytes containing iron. Clearly, the study of Bories et al 1 provides an important step in translational atherosclerosis research by functionally characterizing human atherosclerotic plaque M2 polarized macrophages. Furthermore, their earlier work demonstrated the possibility of promising therapeutic opportunities to diagnose and treat human atherosclerosis.…”

“…22 However, the current report demonstrates that CD68 + MR + M2 polarized macrophages have high iron storage capacity concomitant with a generally atheroprotective phenotype. Bories et al 1 show that by being more efficient in iron handling, the potential atheroprotective effects of M2 macrophages could be attributed, in part, to an increase in heme oxygenase (HO-1), previously shown to be atheroprotective in macrophages 23 by generation of anti-inflammatory carbon monoxide and antioxidant biliverdin from heme catabolism. 24 However, M2 macrophages are also known to produce IL-10 and other anti-inflammatory cytokines, 4 and the present study raises the question of the relevance of LXRα activation by iron loading in mediating these effects.…”

“…I n this issue of Circulation Research, Bories et al 1 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.…”

Human Alternative Macrophages Populate Calcified Areas of Atherosclerotic Lesions and Display Impaired RANKL-Induced Osteoclastic Bone Resorption Activity

“…22 However, the 24 We previously reported the presence of CD68 + MR + alternative macrophages in human atherosclerotic plaques in areas surrounding the lipid-rich area 25 and in iron-rich neovascularized zones. 26 Because previous studies reported the presence of CD68 + macrophages in zones surrounding the calcified areas of human atherosclerotic plaques, 27 the objective of this study was to characterize the functional phenotype of these macrophages.…”