Krüppel-like factor 4 regulates macrophage polarization

• Published in: The Journal of clinical investigation Vol. 121; no. 7; pp. 2736 - 2749
• Main Authors: Liao, Xudong, Sharma, Nikunj, Kapadia, Fehmida, Zhou, Guangjin, Lu, Yuan, Hong, Hong, Paruchuri, Kaavya, Mahabeleshwar, Ganapati H, Dalmas, Elise, Venteclef, Nicolas, Flask, Chris A, Kim, Julian, Doreian, Bryan W, Lu, Kurt Q, Kaestner, Klaus H, Hamik, Anne, Clément, Karine, Jain, Mukesh K
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.07.2011
• Subjects: Adipose Tissue - cytology; Adipose Tissue - physiology; Animals; Biomedical research; Body fat; Cell Line; Cell Polarity; Cytokines; Escherichia coli - immunology; Gene Expression; Genotype & phenotype; Humans; Insulin resistance; Insulin Resistance - physiology; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Lipopolysaccharides - pharmacology; Macrophage Activation - drug effects; Macrophage Activation - immunology; Macrophages - cytology; Macrophages - drug effects; Macrophages - immunology; Mice; Mice, Knockout; NF-kappa B - metabolism; Obesity; Obesity - physiopathology; STAT6 Transcription Factor - genetics; STAT6 Transcription Factor - metabolism; Weight control; Wound Healing - physiology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI45444

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.