title: 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.
authors.affiliation: Case Cardiovascular Research Institute, Department of Medicine, Harrington-McLaughlin Heart and Vascular Institute,University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Xudong
authors.initials: X
authors.lastname: Liao
authors.forename: Nikunj
authors.initials: N
authors.lastname: Sharma
authors.forename: Fehmida
authors.initials: F
authors.lastname: Kapadia
authors.forename: Guangjin
authors.initials: G
authors.lastname: Zhou
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
authors.forename: Hong
authors.initials: H
authors.lastname: Hong
authors.forename: Kaavya
authors.initials: K
authors.lastname: Paruchuri
authors.forename: Ganapati H
authors.initials: GH
authors.lastname: Mahabeleshwar
authors.forename: Elise
authors.initials: E
authors.lastname: Dalmas
authors.forename: Nicolas
authors.initials: N
authors.lastname: Venteclef
authors.forename: Chris A
authors.initials: CA
authors.lastname: Flask
authors.forename: Julian
authors.initials: J
authors.lastname: Kim
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Doreian
authors.forename: Kurt Q
authors.initials: KQ
authors.lastname: Lu
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.forename: Anne
authors.initials: A
authors.lastname: Hamik
authors.forename: Karine
authors.initials: K
authors.lastname: Clément
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000502:physiology; D000818:Animals; D002460:Cell Line; D016764:Cell Polarity; D004926:Escherichia coli / Q000276:immunology; D015870:Gene Expression; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000503:physiopathology; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050800:STAT6 Transcription Factor