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Page 4 of 20 Orekhov et al. Vessel Plus 2019;3:10 I http://dx.doi.org/10.20517/2574-1209.2019.04
[16]
inflammatory cytokine IL-10 . It can be postulated that GM-CSF-induced macrophages belong to M1, and
[17]
M-CSF-induced - to M2-like phenotype .

Moreover, M-CSF can also drive differentiation of monocytes to naïve M0 (M2-like) macrophages that can
[18]
be subsequently polarized to pro- or anti-inflammatory phenotypes by the different activating stimuli .
Therefore, M1 macrophages can be induced directly by GM-SCF or by stimulation of M0 cells with
inflammatory factors. Human-specific pro-inflammatory M4 macrophages can be induced by chemokine
C-X-C motif ligand 4 (CXCL4) and are phenotypically distinct from M1 and M2 macrophages due to
the weak phagocytic capacity, increased resistance to foam cell formation, down-regulated expression of
hemoglobin scavenger receptor CD163, and elevated expression of matrix metalloproteinases (MMP)-7 and
MMP-12 [19,20] .

Exposure of M0 to Th2 cytokines IL-4/IL-13 leads to the formation of classical alternatively activated
M2a macrophages. Immune complexes, lipopolysaccharide (LPS) and IL-1β induce M0 polarization to
M2b phenotype, while anti-inflammatory agents such as IL-10, transforming growth factor β (TGF-β) or
[21]
glucocorticoid hormones promote the conversion of M0 macrophages to M2c . Furthermore, murine M1
macrophages exhibit IL-4 receptor-independent phenotypic switch to vascular endothelial growth factor-
[22]
and IL-10-producing M2d macrophages in the presence of adenosine . In summary, macrophages are fully
differentiated cells that, however, show significant phenotypic plasticity in response to dynamically changing
[23]
tissue environment .
Functional and phenotypic plasticity of macrophages is essential for successful healing of tissue injury
and elimination of infection. In the inflamed site, M1 macrophages are involved in fighting and killing
pathogens/cancer cells and further removal of dead cells and cell debris. M1 macrophages strongly
contribute to the recruitment of monocytes and lymphocytes to the site of injury. When the injured site is
cleared, M1 macrophages do not disappear but undergo a phenotypic switch to M2 macrophages in response
to anti-inflammatory signals that are responsible for resolving inflammation and inducing tissue repair and
[24]
remodeling in a pathogen-free microenvironment . M1-M2 switching also helps to avoid excessive influx of
[25]
pro-inflammatory immune cells to the inflamed site .

UPDATES TO MACROPHAGE CLASSIFICATION
In the recent years, macrophage classification was updated to reflect the complexity of the identified
macrophages subtypes. The proposed nomenclature takes into account the activation signal) that drive
[26]
monocytes differentiation . According to this classification, macrophages with best pronounced features of
M1 phenotype are induced by interferon (IFN)-γ both in mice and humans. Noteworthy, human and murine
IFN-γ-induced macrophage transcriptomes differ by the activation of suppressor of cytokine signaling
cytokines (SOCS) in mouse cells that inhibit their polarization to the anti-inflammatory M2-like phenotype.
In humans, IFN-regulatory factor (IRF)-5 is a major regulator in the inflammatory polarization to the
M(IFN-γ) subset.

The exposure of naïve (M0) macrophages to LPS or a combination of LPS and IFN-γ results in the formation
of the M2-like macrophage phenotypes that seem to be less pro-inflammatory than the macrophage
subset generated under influence of IFN-γ alone. In the presence of LPS+IFN-γ or LPS alone, phenotypic
[27]
polarization of macrophages is mediated by STAT1 . In addition, in both murine LPS+IFN-γ- or LPS-
induced macrophages, SOCS1 and NF-κB inhibitor ζ (NDKBIZ) are involved in polarization of murine
[26]
monocytes to these macrophage sub-populations . NDKBIZ is induced by LPS and serves as a conductor
of the pro-inflammatory effect of LPS by the interaction with other NF-B proteins via C-terminal ankyrin-
[28]
repeat domains . In humans, STAT-1, IRF-1, and IRF-5 drive the polarization towards the LPS+IFN-γ-
induced phenotype, while IRF-5 alone is primarily involved in the transcriptional control of polarization to