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Page 6 of 20 Orekhov et al. Vessel Plus 2019;3:10 I http://dx.doi.org/10.20517/2574-1209.2019.04

the IFN-stimulated gene factor 3 complex to drive transcription of target genes from the regulatory IFN-
[39]
stimulated response elements .

Experiments involving genetic deletion/inactivation of STAT-1 showed great significance of this
transcriptional activator for induction of M1-mediated pro-inflammatory responses. STAT-1-deficient mice
had limited capacity to remove pathogens and decreased resistance against Listeria monocytogenes, an
infectious bacterium. In macrophages lacking STAT-1, Type I IFN- and IFN-γ-dependent responses were
greatly reduced and impaired resulting in the loss of IFN-β production, Type I IFN-dependent signaling and
[40]
generation of M1 phenotype . STAT-2-deficient mice exhibited defects in antiviral immune response due to
[41]
the absence of Type I IFN autocrine/paracrine signaling .
However, the role of STAT-2 in IFN-γ signaling is probably dispensable since could be partially compensated
by STAT-1 that is able to form transcriptionally active homodimers and drive expression of IFN-γ target
[41]
genes including IRF-1 and major histocompatibility complex (MHC) class I . In STAT2-deficient mice,
IFN-α is able to induce MHC class II expression due to the dysfunctionality of the inhibitory feedback loop
in response to Type I IFN. This feedback mechanism is mediated by SOCS1, which prevents Jak1-dependent
[42]
phosphorylation of STAT-2 .
Role of IRF signaling in M1 differentiation
IRF family contains 9 members that perform different signaling functions. Several of them, IRF-1 to IRF-
5 and IRF-8 play key roles in macrophage polarization. Pro-inflammatory macrophage polarization largely
depends on IRF-5, which can play a decisive role in choosing the pro- or anti-inflammatory polarization
[43]
pathways . The expression of IRF-5 is stimulated by GM-CSF and can be induced by the activation of
[44]
TLR and other pattern-recognizing receptors during infection . Activation of the nucleotide-binding
oligomerization domain-containing protein 2 receptor leads to the IRF-5 up-regulation due to receptor-
[45]
interacting serine-threonine kinase 2 (RIPK2)-mediated phosphorylation . IRF-5 transcriptional activity
[46]
can be also stimulated by inhibitor of NF-κB kinase subunit β (IKK-β) and TANK-binding kinase 1
[45]
(TBK1) .
IRF-1 is another IRF involved in pro-inflammatory polarization of macrophages. Its expression is low in
[47]
resting macrophages and can be up-regulated by IFN-γ upon M1 polarization . The activation of IRF-1
[48]
[49]
is promoted by casein kinase II and inhibited by IκB kinase-ε NF-κB . The effects of IRF-1 include up-
regulation of pro-inflammatory genes, which can be mediated by cooperation with NF-κB and c-Jun, known
[50]
as “enhansosome” formation NF-κB . In murine macrophages, IRF-1 and IRF-2 were shown to regulate
[51]
LPS-induced expression of TLRs . At the same time, IRF-1 and IRF-2 can transcriptionally repress the
[52]
expression of anti-inflammatory (M2) genes, as was shown for IL-4 .
IRF-8 is characterized by a weak interaction with chromatin in macrophage nucleus, which can, however, be
[53]
strengthened following interaction with PU.1, IRF-1 or IRF-2, which reduces its mobility . Such interaction
[54]
can occur as a result of LPS stimulation, and results in up-regulation of a number of target genes .
Among the pro-inflammatory genes induced by IRF-8 are IL-12p40, IL-12p35, IFN-β, and iNOS, that are
[55]
characteristic for the M1 macrophage phenotype . The enhancement of IRF-8 function as transcription
activator can occur via its ubiquitinilation in an E3 ubiquitin ligase tripartite-motif 21 (TRIM21)-dependent
[57]
[56]
manner . By contrast, sumoylation of IRF-8 increases its activity as transcription repressor .
IRF-2 recognizes the same regulatory elements in the promoters of target genes as IRF-1 and can act as
[58]
its competitive inhibitor . At the same time, IRF-2 can play a role of activator for IRF8, leading to the
[54]
induction of neurofibromin 1 (NF1) transcription . Like IRF-8, IRF-2 is regulated by sumoylation, which
[59]
enhances its transcriptional suppressor function . The role of IRF-2 in macrophage polarization is not