Krüppel-like factor 4 regulates macrophage polarization
Xudong Liao, … , Karine Clément, Mukesh K. Jain
Xudong Liao, … , Karine Clément, Mukesh K. Jain
Published June 13, 2011
Citation Information: J Clin Invest. 2011;121(7):2736-2749. https://doi.org/10.1172/JCI45444.
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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

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

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Figure 1

Klf4 expression is augmented by M2 and inhibited by M1 stimuli in macrophages.

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Klf4 expression is augmented by M2 and inhibited by M1 stimuli in macro...
(A and B) KLF mRNA levels in (A) mouse PMs and (B) BMDMs after 16 hours of stimulation with LPS (50 ng/ml) or mouse IL-4 (5 ng/ml). Gene expression levels were assessed by qPCR and normalized to those in untreated cells (dashed line). Klf1, Klf15, and Klf17 were not detectable in PMs or BMDMs. Klf5 and Klf14 were not detectable in BMDMs. n = 5. (C and D) KLF4 protein levels after LPS and IL-4 treatment. n = 3. (E) KLF4 mRNA level in M-CSF–differentiated primary human macrophages (from 3 donors) stimulated with LPS (50 ng/ml) or human IL-4 (10 ng/ml) for 16 hours. (F) IL-4–mediated induction of the Klf4 gene was diminished in Stat6-null PMs and BMDMs. n = 3. C57BL/6J mice were used as control (WT). *P < 0.05, Student’s t test.