Changes in transcriptome of macrophages in atherosclerosis

Abstract

Macrophages display significant phenotypic heterogeneity. Two growth factors, macrophage colony-stimulating factor and chemokine (C-X-C motif) ligand 4, drive terminal differentiation of monocytes to M0 and M4 macrophages respectively. Compared to M0 macrophages, M4 cells have a unique transcriptome, with expression of surface markers such as S100A8, mannose receptor CD206 and matrix metalloproteinase 7. M4 macrophages did not express CD163, a scavenger receptor for haemoglobin/haptoglobin complex. Depending on the stimuli, M0 macrophages could polarize towards the proinflammatory M1 subset by treatment with lipopolysaccharide or interferon-γ. These macrophages produce a range of proinflammatory cytokines, nitric oxide, reactive oxygen species and exhibit high chemotactic and phagocytic activity. The alternative M2 type could be induced from M0 macrophage by stimulation with interleukin (IL)-4. M2 macrophages express high levels of CD206 and produce anti-inflammatory cytokines IL-10 and transforming growth factor-β. M1, M2 and M4 macrophages could be found in atherosclerotic plaques. In the plaque, macrophages are subjected to the intensive influence not only by cytokines and chemokines but also with bioactive lipids such as cholesterol and oxidized phospholipids. Oxidized phospholipids induce a distinct Mox phenotype in murine macrophages that express a unique panel of antioxidant enzymes under control of the redox-regulated transcription factor Klf2, resistant to lipid accumulation. In unstable human lesions, atheroprotective M(Hb) and HA-mac macrophage subsets could be found. These two subsets are induced by the haemoglobin/haptoglobin complex, highly express haeme oxygenase 1 and CD163, and are implicated in clearance of haemoglobin and erythrocyte remnants. In atherogenesis, the macrophage phenotype is plastic and could therefore be switched to proinflammatory (i.e. proatherogenic) and anti-inflammatory (i.e. atheroprotective). The aim of this review was to characterize changes in macrophage transcriptome in atherosclerosis and discuss key markers that characterize different phenotypes of macrophages present in atherosclerotic lesions.

Keywords: atherogenesis; atherosclerosis; macrophages; phenotypic heterogeneity; transcriptome.

Figure 1

Adhesion of monocytes to the luminal endothelium that covers a fatty streak (A) and the accumulation of oxidized lipoproteins of low density (oxLDL) in macrophages in an in vitro experiment (B and C); incubation of macrophages with oxLDL is accompanied by the formation of foam cells (D) . (A) Scanning electron microscopy. (B and C) Oxidized LDL were labelled with gold particles. (D) Transmission electron microscopy. Scale bars = 3 μm (A), 250 nm (B and C), 1 μm (D).

Figure 2

Phenotypes of macrophages in atherosclerotic lesions. In the subendothelial layer, monocytes could differentiate to various macrophage subtypes depending on the microenvironmental stimuli. Solid arrows indicate monocyte–macrophage differentiation, whereas dotted arrows indicate macrophage polarization. M-DC: dendritic cells; Mox: foam cells induced by oxidized low-density lipoproteins (oxLDL); HA-Mac: haemorrhage-associated macrophages; CXCL4: chemokine (C-X-C motif) ligand 4; IL: interleukin; IFN-γ: interferon-γ; LPS: lipopolysaccharide; M-CSF: macrophage colony-stimulating factor; GM-CSF: granulocyte–macrophage colony-stimulating factor.