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.
Highlights
Monocyte–macrophage differentiation Macrophage polarization Macrophage phenotypes in atherosclerosis Changes in macrophage transcriptome during differentiation and polarization – Monocyte–macrophage differentiation– ‘Classical’ polarization of M0 macrophages to M1 – ‘Alternative’ polarization of M0 macrophages to M2 – CXCL4-induced M4 macrophages – Cholesterol load – Mox macrophages Conclusion AbstractMacrophages display significant phenotypic heterogeneity
In atherosclerotic lesions of low-density lipoprotein receptor (Ldlr)-deficient mice, Mox macrophages were shown to be widely presented accounting for 30% of all plaque macrophages, whereas M1 and M2 subsets accounted for 40% and 20% respectively [39]
Martinez et al [11] found the second cluster of 478 genes (1.2%) with significant changes in the expression during differentiation that maintained in mature macrophages and were resistant to polarizing signals
Summary
Atherosclerosis is characterized by accumulation of modified serum lipids and lipoproteins in the arterial intima [1]. HA-mac, M(Hb) and Mhem macrophages could be found in haemorrhagic zones of unstable lesions where they phagocytize and utilize erythrocyte remnants and haemoglobin deposits These macrophages are atheroprotective and resistant to transformation to foam cells because of high expression of nuclear receptors LXRa and LXRb and transporters ABCA1 and ABCG1 responsible for cholesterol efflux [32]. Transcription factor Nurr could be induced in macrophages in response to inflammatory signals and leads to the inhibition of expression of proinflammatory genes through suppressing the activity of NF-jB [58] This factor plays the atheroprotective role by decreasing lipid loading in plaque macrophages [89]. Expression of Vegfa could suggest for a putative involvement of Mox macrophages to intraplaque neovascularization, whereas up-regulation of Trib could indicate
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