Page 108 - Read Online

Orekhov et al. Vessel Plus 2019;3:10 I http://dx.doi.org/10.20517/2574-1209.2019.04 Page 13 of
20
macrophages, with the prominent role of KLF6 in M1 polarization and KLF4 in the generation of M2
phenotype.

NUCLEAR FACTOR (ERYTHROID-DERIVED 2)-LIKE 2
Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor which belongs to the family of
bZIP proteins [150] regulating antioxidant proteins that protect against oxidative stress triggered by injury
and inflammation [151] . Nrf2 is highly expressed in hematopoietic progenitors and cells of the myeloid
lineage [152] . In its inactive state in the absence of stimuli, Nrf2 has a cytoplasmic localization as a complex
with two other proteins, an adaptor Kelch like-ECH-associated protein 1 (KEAP1) and ubiquitin ligase
cullin 3 [153] . Cullin 3 mediates Nrf2 degradation through the mechanism of ubiquitination facilitated by
KEAP1. Ubiquitinated Nrf2 then is transported to the proteasome where it is degraded. Oxidative stress or
electrophile stress abolishes critical cysteine residues in the KEAP1 molecule thereby causing liberation of
Nrf2 from the repressive complex [154] . Nrf2 then moves to the nucleus where it assembles with c-Maf and
initiates transcription of target genes from the antioxidant response element [155] .

Among Nrf2-dependent targets are numerous antioxidant genes, including heme oxygenase (HO-
1), NAD(P)H quinone oxidoreductase 1, sulforedoxin 1 (SRXN1), thioredoxin reductase 1 (TXNRD1),
glutamate-cysteine ligase (catalytic and modifier subunits), glutathione S-transferases, and UDP-
glucuronosyltransferases. Nrf2-mediated up-regulation of expression of these genes leads to the mobilization
of the intracellular cytoprotective antioxidant and detoxifying system. In macrophages, Nrf2 is an important
redox regulator of inflammatory activation and polarization [156] . In response to plaque lipids (i.e., oxidized
phospholipids), Nrf2 mediates transformation of macrophages to a new phenotype (Mox) expressing
large amounts of HO-1 and other Nrf2-dependent antioxidant genes, as well as IL-1β and IL-10 [157] . Nrf2
appears to be important for the induction of HO-1 overproduction observed in anti-inflammatory M2 and
Mhem macrophages [151] . By contrast, BTB and CNC homolog 1 (Bach1), a DNA-binding factor, acts as a
transcriptional repressor of HO-1 expression [158] . Heme binding to Bach1 induces derepression of the HO-1
gene and promotes recruitment of Nrf2 to the HO-1 promoter [159] . Therefore, redox signaling and heme
are crucially involved in the Nrf2-dependent up-regulation of HO-1. Induction of HO-1 stimulates several
pathways including production of the anti-inflammatory compounds bilirubin and carbon monoxide,
which contribute to the phenotypic switch of macrophages towards M2 [160] . In macrophages, Nrf2 primes
expression of several ATP-binding cassette (ABC) transporters involved in bile and cholesterol efflux [161] . M2
macrophages and specialized heme/iron-handling macrophage subsets such as HA-mac, M(Hb), and Mhem
[23]
exhibit increased the expression of ABC transporters .
Therefore, Nrf2 primes the anti-inflammatory polarization of macrophages in response to oxidative injury
and plaque lipids. Induction of Nrf2 in response to oxidative stress has a cytoprotective and cardioprotective
effect since this factor is involved in the generation of anti-atherogenic macrophage subsets that are
involved in hemoglobin/heme/iron utilization and recycling thereby decreasing the intraplaque oxidative
stress and damage [162] . However, in the microenvironment rich in oxidative low-density lipoprotein and
pro-inflammatory cytokines, Nrf2 up-regulation may have pro-atherosclerotic consequences because it
stimulates expression of several iron-metabolizing genes such as HO-1, ferroportin, ferritin, and hepcidin
that increases iron trapping and oxidative stress in macrophages, enhances lipid accumulation and formation
of foam cells [163,164] .

CONCLUSION
In this review, we considered a role of principal transcriptional regulators in either M1 or M2 differentiation
of macrophages. The transcriptional regulation of macrophage plasticity in response to various stimuli
is very complex and involves global changes in the macrophage transcriptome. There are many key