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Page 12 of 20 Orekhov et al. Vessel Plus 2019;3:10 I http://dx.doi.org/10.20517/2574-1209.2019.04

the induction of macrophage differentiation towards M2 [134] . PPAR-δ activity is induced and mediated by
the IL-4/STAT-6 axis [135] . PPAR-δ agonists promote the development of the anti-inflammatory IL-4-like
morphological phenotype in macrophages. Activation of PPAR-δ induces the repression of multiple NFκ-B
and STAT-1-dependent inflammatory genes along with down-regulation of immunosuppressive molecules
such as IDO, programmed cell death ligand, and inhibitory Fcγ receptor IIB thereby suggesting that PPAR-
δ-primed macrophages possess anti-inflammatory, but not immunoregulatory (i.e., immunosuppressive)
properties [136] . Unlike PPAR-γ, activated PPAR-δ is unable to induce classical M2 macrophages from
monocytes [137] indicating a major involvement of PPAR-γ. The role of PPAR-δ is rather more important in the
metabolic control. Accordingly, PPAR-δ deficiency was associated with obesity, insulin resistance, and fatty
liver disease [134] .

KRÜPPEL-LIKE FACTORS
Krüppel-like factors (KLFs) belong to the family of zinc-finger DNA-binding proteins that have three
characteristic zinc fingers on the C-terminus. Among multiple KLF members, KLF2, KLF4, and KLF6 are
involved in the transcriptional control of monocyte/macrophage activities [117] . IL-4-induced STAT-6 and
KLF-4 suppress M1 polarization through inhibition of NF-κB and KLF-4-dependent induction of MCP-1-
induced protein, which in turn stimulates CCAAT/enhancer-binding protein-β and PPAR-γ to promote M2
polarization [138,139] . KLF2/4-induced impairment of NF-κB function involves alteration of the recruitment of
the NF-κB coactivator complex p300/CBP-associated factor (PCAF)/p300 to the target promoter [140] . KLF2/4-
deficient macrophages are especially prone to M1 polarization upon LPS challenge followed by increased
antimicrobial activity. Targeted KLF2 deletion in murine myeloid cells is associated with greater sensitivity
of mice to LPS-induced sepsis, acute inflammatory responses, and increased pathogen clearance in an
experimental peritonitis model [141] . Low density lipoprotein-receptor (Ldlr)-deficient mice with specific
myeloid deletion of KLF2 showed advanced atherosclerosis indicating the atheroprotective role of KLF2 in
myeloid cells, which suppresses inflammatory polarization of macrophages in atherosclerotic lesions [142] .
However, KLF4 deficiency in mammary tumor cells led to diminished tumor growth and expansion due
to impaired pro-metastatic function of myeloid-derived suppressor cells suggesting a role of KLF4 in
tumorogenesis [143] .

Although both KLF2 and KLF4 have synergistic effects in dampening pro-inflammatory activity in
macrophages, the outcomes of their activity on the differentiation towards M2 are different. KLF4-deficient
macrophages exhibited altered expression of M2-specific markers in response to IL-4/IL-13 while KLF2-
deficient macrophages did not [138,141] . Thus, KLF4 is primarily involved in IL-4-dependent polarization of
macrophages towards M2, while the role of KLF2 appears to be less significant.

Myeloid KLF2 is a negative regulator of HIF-1α expression since this factor inhibits NF-κB-dependent
HIF-1α expression. Hypoxia or exposure to bacterial products/endotoxins reduces KLF2 expression in
macrophages thereby promoting expression HIF-1α and HIF-1α-inducible targets [141] . These findings show
a crucial role of HIF-1α/KLF2 balance in the regulation of myeloid cell inflammatory responses in hypoxic
and normoxic conditions [144,145] .

In contrast to KLF2 and KLF4, KLF6 positively regulates pro-inflammatory phenotype in macrophages.
KLF6 is up-regulated by pro-inflammatory stimuli such as LPS and IFN-γ but is suppressed by Th2 cytokines
IL-4 and IL-13. During M1 polarization, KLF6 cooperates with NF-κB in potentiating transcription of
inflammatory genes [146] and inhibits PPAR-γ expression [147] . KLF6 can also prevent PPAR-γ binding to the
promoters of target genes, including CCL20 [148] and thioredoxin-interacting protein (TXNIP) [149] .

In summary, the KLF family of transcription factors exhibits diverse effects on M1/M2 activation of