Krüppel-like factor 4 regulates macrophage polarization

Xudong Liao, Nikunj Sharma, Fehmida Kapadia, Guangjin Zhou, Yuan Lu, Hong Hong, Kaavya Paruchuri, Ganapati H. Mahabeleshwar, Elise Dalmas, Nicolas Venteclef, Chris A. Flask, Julian Kim, Bryan W. Doreian, Kurt Q. Lu, Klaus H. Kaestner, Anne Hamik, Karine Clément, Mukesh K. Jain

Research output: Contribution to journalArticlepeer-review

399 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2736-2749
Number of pages14
JournalJournal of Clinical Investigation
Volume121
Issue number7
DOIs
StatePublished - Jul 2011

ASJC Scopus subject areas

  • Medicine(all)

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