Krüppel-like factor 4 regulates macrophage polarization

Abstract

Current paradigms suggest that two macrophage subsets, termed M1 and M2, are involved in inflammation and host defense. While the distinct functions of M1 and M2 macrophages have been intensively studied -the former are considered proinflammatory and the latter antiinflammatory -the determinants of their speciation are incompletely understood. Here we report our studies that identify Krüppel-like factor 4 (KLF4) as a critical regulator of macrophage polarization. Macrophage KLF4 expression was robustly induced in M2 macrophages and strongly reduced in M1 macrophages, observations that were recapitulated in human inflammatory paradigms in vivo. Mechanistically, KLF4 was found to cooperate with Stat6 to induce an M2 genetic program and inhibit M1 targets via sequestration of coactivators required for NF-κB activation. KLF4-deficient macrophages demonstrated increased proinflammatory gene expression, enhanced bactericidal activity, and altered metabolism. Furthermore, mice bearing myeloid-specific deletion of KLF4 exhibited delayed wound healing and were predisposed to developing diet-induced obesity, glucose intolerance, and insulin resistance. Collectively, these data identify KLF4 as what we believe to be a novel regulator of macrophage polarization.

CREB pathway links PGE2 signaling with macrophage polarization

“…We evaluated the effect of cAMP signaling on the expression of M2 macrophage marker genes, including arginase-1 (Arg1), the mannose receptor (Mrc1), resistin-like α (Fizz1, Retnla), and chitinase 3-like 3 (Ym1, Chi3l3) in cultured bone marrow macrophages (BMMs) (12,13). Exposure to PGE2, potentiated IL-4-induced increases in M2 marker gene expression ( Fig.…”

“…In this regard, KLF4 has been shown to cooperate with STAT6 in promoting M2 macrophage polarization; deletion of the KLF4 gene in macrophages disrupts M2 function and increases proinflammatory gene expression (13). Moreover, the mouse KLF4 promoter contains CREB binding sites at −269 and −232 relative to the transcription start site.…”

Merck Ad5/HIV induces broad innate immune activation that predicts CD8 + T-cell responses but is attenuated by preexisting Ad5 immunity

“…Interestingly, a number of the MRKAd5-specific genes are also associated with immunoregulatory functions. Among these, KLF4 promotes anti-inflammatory "M2" and inhibits proinflammatory "M1" macrophage polarization (35), and PDCD1LG2 and IDO1 suppress T-cell activation through a variety of mechanisms (55,56). Further study will determine whether pharmacological inhibition of these molecules will lead to enhanced Ad5-induced T-cell functionality.…”

Nuclear Receptor Nr4a2 Promotes Alternative Polarization of Macrophages and Confers Protection in Sepsis

“…STAT6 and CCAAT/enhancer-binding protein ␤ (C/EBP␤) are recruited at an enhancer 3 kb upstream of the transcription start site to regulate arginase 1 expression in response to . STAT6 also acts in synergy with KLF4 to regulate arginase 1 expression; however, arginase 1 expression in response to Bacillus Calmette-Guérin (BCG) is STAT6-independent and depends only upon CCAAT/enhancer-binding protein ␤ transcriptional activity (13,49). PU.1 is also known to bind to the arginase 1 promoter at two sites, one in the enhancer region 3 kb upstream of transcription start site and another 700 bp upstream of the basal promoter (48,50).…”