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Page 2 of 20 Orekhov et al. Vessel Plus 2019;3:10 I http://dx.doi.org/10.20517/2574-1209.2019.04

monocyte-to-macrophage differentiation involves global transcriptome changes that are tightly controlled by various
transcriptional regulators and signaling mechanisms. In this review, we discuss monocyte-macrophage heterogeneity and
signaling pathways regulating the differentiation at transcription level.

Keywords: Monocyte, macrophage, differentiation, polarization, inflammatory M1 phenotype, anti-inflammatory M2 phenotype,
transcriptional regulation

INTRODUCTION
Being a key component of the innate immunity, macrophages are involved in phagocytosis and clearance
of cell debris, invading microorganisms, foreign bodies, modified or damaged cells, and other objects
[1]
and substances that do not express on their surface markers specific for normal body cells . Initially, 2
major phenotypes of macrophages have been distinguished: pro-inflammatory M1 phenotype, and anti-
inflammatory M2 phenotype. This simplified classification reflected a similar distinction between Th1
and Th2 lymphocytes. M1 macrophages release cytokines and chemokines essential for activation and
recruitment of lymphocytes to the inflamed sites. Macrophages also perform antigen-presenting function
[2]
essential for the induction of the humoral immune response . Alternatively-activated M2 macrophages
control and resolve inflammation through releasing anti-inflammatory cytokines. These macrophages
[2]
participate in wound healing, post-inflammatory tissue repair and remodeling . While M1 activity
suppresses cell proliferation and promotes tissue damage, M2 activity induces tissue regeneration and
stimulates cells to proliferate. The differences in functional properties of the M1 and M2 macrophage subsets
are reflected by differences in arginine metabolism. M1 macrophages possess a unique capacity to generate
a “killer” molecule nitric oxide (NO) from arginine, which is widely used to damage and kill pathogens
through production of peroxynitrite. By contrast, M2 macrophages transform arginine to the “repair” amino
[3]
acid molecule ornithine, which is further involved in the synthesis of proline and polyamines .
In macrophages, polarization and phenotype switching are accompanied by global changes in cell
transcriptome and proteome that are strictly regulated by exogenous and intrinsic stimuli. Failure to control
macrophage plasticity may result in maladaptive response leading either to inflammatory diseases and tissue
damage (in a case of excessive M1-polarized response) or to tissue fibrosis and cancer (in case of extensive
M2-polarized response).

MONOCYTE HETEROGENEITY
Monocytes that give rise to the tissue macrophage population are also characterized by substantial
heterogeneity, which may underlie that of macrophages. Early studies showed the presence of two main
[4]
+
high
low
+
monocyte subsets in mice . Pro-inflammatory monocytes (characterized as Gr1 /Ly6C CCR2 CX3CR1 )
can give rise to inflammatory macrophages and dendritic cells, while anti-inflammatory monocytes (Gr1/
-
high
low
[5]
-
Ly6C CCR2 CX3CR1 ) perform patrolling functions and differentiate to M2 macrophages . It was
hypothesized that the occurrence of such subsets that serve as precursors of either pro-inflammatory or
anti-inflammatory macrophages can suggest for the presence of two distinct or overlapping mechanisms
in monocyte differentiation. However, this hypothesis remains to be confirmed experimentally. Recently,
low
high
Ly6C monocytes were shown to serve as precursors of Ly6C cells in homeostatic conditions when
transplanted to the control mice being able to spontaneously differentiate to Ly6C cells both in the blood
low
[6]
high
and in bone marrow . In the absence of inflammation, Ly6C monocytes migrate and accumulate in the
[6,7]
high
low
bone marrow where they transform to the Ly6C sub-population . Functionally, the Ly6C subset is
low
involved in restoration of tissue-specific resident macrophages and replenishment of Ly6C monocytes (in
steady-state conditions) or induction of inflammation and antigen processing (in inflammatory conditions).
low
Apart from patrolling, Ly6C monocytes participate in anti-viral response thanks to their ability to
[8]
recognize viral nucleic acids due to high expression of toll-like receptor (TLR)-7 . This subset can also be