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

Bacterial invasion commonly leads to oxygen deprivation and induction of hypoxic conditions in the local
environment. Pro-inflammatory macrophages are resistant to oxygen tissue deficits in part due to the
metabolic preference to use glycolysis, which does not require aerobic conditions [104] . It appears that hypoxia
and hypoxia-inducible factors (HIF) trigger inflammatory/anti-inflammatory activation of macrophages [105] .

Th1 cytokines induce the activity of HIF-1α isoform during M1 macrophage activation whereas Th2
cytokines stimulate HIF-2α up-regulation during M2 formation [106] . NF-κB is involved in the induction of
HIF-1α, which in turn stimulates the expression of iNOS. Even in normoxic conditions, HIF-1α continues
to induce NO production in macrophages along with other molecules, including TNF-α, antimicrobial
peptides, and endoproteases such as granzyme B, indicating that hypoxia is not mandatory for HIF-1α up-
regulation [106] . In mice, HIF-1α deficiency is associated with weakened antimicrobial responses in myeloid
immune cells that cannot prevent systemic expansion of bacterial infection [107] .

In contrast to HIF-1α, HIF-2α controls the expression of arginase-1, which restricts the NO production in
macrophages by limiting the substrate availability [108] . With regard to tryptophan metabolism, which is a
hallmark of either M1 or M2 macrophage phenotypes, HIF-2α antagonizes HIF-2α by inducing arginase-1-
dependent production of ornithine, urea, and polyamines, resulting in a M2-specific metabolic signature.

HIF-1α controls the glycolytic capacity in myeloid cells, and its deficiency leads to depletion of the cellular
ATP pool. Indeed, HIF-1α deficient macrophages exhibit decreased cell motility, phagocytic capacity,
aggregation, and bacterial killing due to serious metabolic impairments [109] . Therefore, HIF-1α is essential
for survival and efficient function of macrophages in the inflammatory microenvironment. Myeloid-specific
deletion of HIF-2α does not seem to affect the intracellular ATP levels suggesting for a dispensable role of
this factor in the metabolic control. Tumor-associated macrophages have elevated expression of HIF-2α, which
supports their migration (through induction of M-CSFR and CXCL4), expression of anti-inflammatory
cytokines such as IL-10, and increased invasiveness [110] .

STEROID HORMONE RECEPTORS
Glucocorticoid hormones are important regulators of gene expression associated with binding of activated
steroid hormone receptors (SHRs; also known as glucocorticoid receptors) to hormone response elements
(HREs) in the target promoters. SHRs are homodimeric nuclear receptors produced in the adrenal glands
in response to stress signals such as infection, injury or starvation [111] . In normal non-stressful conditions,
circadian rhythms regulate SHR production for supporting systemic homeostasis [112] . Exposure to
glucocorticoids can induce the M2c phenotype characterized by high expression of arginase-1 (in mice),
mannose receptor (in humans), IL-10, pattern-recognition receptor pentraxin-3, Mer receptor kinase
(MerTK) essential for efferocytosis. M2c cells, which possess anti-inflammatory and immunoregulatory
properties, are involved in the inflammation resolution, regulatory T cells induction, phagocytosis of
apoptotic cells, and wound healing [113,114] .

Human macrophages activated with glucocorticoids release anti-inflammatory cytokines IL-4, IL-10 while
having a decreased production of pro-inflammatory cytokines. The expression of a scavenger receptor
CD163, which binds hemoglobin-haptoglobin complexes, is up-regulated in such cells. In glucocorticoid-
treated macrophages, expression of IL-1RII, a decoy receptor for IL-1, is also up-regulated. Activity of AP1
and NF-κB is reduced thereby leading to suppression of expression of pro-inflammatory genes [115] . Like M1
macrophages, these macrophages maintain high mobility and are able to migrate quickly into inflamed
tissue where they may implicate their unique anti-inflammatory and scavenging properties to inhibit
inflammation, remove died cells, and induce tissue repair [116] .

Anti-inflammatory properties of SHRs affect a variety of inflammatory signaling mechanisms. SHRs inhibit