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

Abstract

Rationale: Vascular calcification is a process similar to bone formation leading to an inappropriate deposition of calcium phosphate minerals in advanced atherosclerotic plaques. Monocyte-derived macrophages, located in atherosclerotic lesions and presenting heterogeneous phenotypes, from classical proinflammatory M1 to alternative anti-inflammatory M2 macrophages, could potentially display osteoclast-like functions.Objective: To characterize the phenotype of macrophages located in areas surrounding the calcium deposits in human atherosclerotic plaques. Methods and Results: Macrophages near calcium deposits display an alternative phenotype being both CD68and mannose receptor-positive, expressing carbonic anhydrase type II, but relatively low levels of cathepsin K. In vitro interleukin-4-polarization of human primary monocytes into macrophages results in lower expression and activity of cathepsin K compared with resting unpolarized macrophages. Moreover, interleukin-4 polarization lowers expression levels of the osteoclast transcriptional activator nuclear factor of activated T cells type c-1, associated with increased gene promoter levels of the transcriptional repression mark H3K27me3 (histone 3 lysine 27 trimethylation). Despite higher expression of the receptor activator of nuclear factor κB receptor, receptor activator of nuclear factor κB ligand/macrophage colony-stimulating factor induction of nuclear factor of activated T cells type c-1 and cathepsin K expression is defective in these macrophages because of reduced Erk/cfos-mediated downstream signaling resulting in impaired bone resorption capacity. Conclusions:

Macrophage Heterogeneity Complicates Reversal of Calcification in Cardiovascular Tissues

“…Monocytes/macrophages can become osteoclast-like cells by the addition of RANKL and M-CSF in vitro; however, they may not differentiate into fully functional osteoclasts in vivo. This incomplete differentiation may result from the presence of either a pro-inflammatory (Nagy et al 8 ) or anti-inflammatory environment (Chinetti-Gbaguidi et al 1 ). A heterogeneous macrophage population may drive cardiovascular calcification though the coexistence of a low potential for mineral resorption and enhanced release of calcific extracellular vesicles (New et al 7 ) contributing to mineral deposition.…”

“…Often thought of as host defense cells with phagocytic, innate/adaptive immune system and pro-inflammatory roles, macrophages contribute to a variety of tissue functions including: adipose thermogenesis, tissue repair, splenic and hepatic iron recycling, neural synaptic pruning, and cardiac electrical conduction. In the current issue of Circulation Research , Chinetti-Gbaguidi et al 1 enhance our understanding of the diverse roles of macrophages in vascular disease by reporting that macrophages near calcified regions of human atherosclerotic lesions display low mineral resorption potential. This study ties macrophage osteoclastogenesis to vascular calcification and identifies disrupted signaling pathways that may help to develop anti-calcification therapies.…”

Macrophage‐derived MMP‐9 enhances the progression of atherosclerotic lesions and vascular calcification in transgenic rabbits

“…If this process was retarded, calcium deposition in the lesions would be enhanced. This notion was supported by the observation that TRAP staining, a histochemical marker for osteoclast differentiation were significantly reduced in atherosclerotic lesions of Tg rabbits compared with non‐Tg rabbits (Figure ). Finally, besides macrophages, vascular smooth muscle cells constitute another cellular source that participates in the vascular calcification.…”

Morphometric characteristics of neovascularization of carotid atherosclerotic plaques

“…По данным некоторых авторов [22,23], появление М2-подобных макрофагов (Mhem) связано не только с кровоизлиянием в бляшку, но и с ее обызвествлением. F. Demeure и соавт.…”