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Pyruvate Dehydrogenase Kinase 1 Participates in Macrophage Polarization via Regulating Glucose Metabolism

Zheng Tan, Na Xie, Huachun Cui, Douglas R. Moellering, Edward Abraham, Victor J. Thannickal and Gang Liu
J Immunol June 15, 2015, 194 (12) 6082-6089; DOI: https://doi.org/10.4049/jimmunol.1402469
Zheng Tan
*Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;
†Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China;
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Na Xie
*Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;
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Huachun Cui
*Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;
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Douglas R. Moellering
‡Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294; and
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Edward Abraham
§Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157
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Victor J. Thannickal
*Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;
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Gang Liu
*Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;
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Abstract

The M1 and M2 polarized phenotypes dictate distinctive roles for macrophages as they participate in inflammatory disorders. There has been growing interest in the role of cellular metabolism in macrophage polarization. However, it is currently unclear whether different aspects of a specific metabolic program coordinately regulate this cellular process. In this study, we found that pyruvate dehydrogenase kinase 1 (PDK1), a key regulatory enzyme in glucose metabolism, plays an important role in the differential activation of macrophages. Knockdown of PDK1 diminished M1, whereas it enhanced M2 activation of macrophages. Mechanistically, PDK1 knockdown led to diminished aerobic glycolysis in M1 macrophages, which likely accounts for the attenuated inflammatory response in these cells. Furthermore, we found that mitochondrial respiration is enhanced during and required by the early activation of M2 macrophages. Suppression of glucose oxidation, but not that of fatty acids, inhibits this process. Consistent with its inhibitory role in early M2 activation, knockdown of PDK1 enhanced mitochondrial respiration in macrophages. Our data suggest that two arms of the glucose metabolism synergistically regulate the differential activation of macrophages. Our findings also highlight the central role of PDK1 in this event via controlling glycolysis and glucose oxidation.

Footnotes

  • G.L. designed and supervised the study; Z.T., N.X., H.C., and D.R.M. performed the experiments and analyzed the data; E.A. and V.J.T. contributed intellectual inputs; and Z.T., E.A., V.J.T., and G.L. wrote the manuscript.

  • This work was supported by National Institutes of Health Grants HL105473 (to G.L.), HL076206 (to G.L.), and HL114470 (to V.J.T.). This work was also supported by University of Alabama at Birmingham Diabetes Research Center Bio-Analytical Redoux Biology Core Grant P30 DK079626 (to D.R.M.).

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    Arg1
    arginase-1
    BMDM
    bone marrow–derived macrophage
    Ct
    cycle threshold
    2-DG
    2-deoxy-d-glucose
    ETO
    etomoxir
    FCCP
    carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone
    FIZZ-1
    found in inflammatory zone 1
    GM-BMM
    GM-CSF–induced macrophage
    HKPA
    heat-killed Pseudomonas aeruginosa
    OCR
    oxygen consumption rate
    PDH
    pyruvate dehydrogenase
    PDK1
    pyruvate dehydrogenase kinase 1
    siRNA
    small interfering RNA
    TCA
    tricarboxylic acid.

  • Received September 26, 2014.
  • Accepted April 7, 2015.
  • Copyright © 2015 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 194 (12)
The Journal of Immunology
Vol. 194, Issue 12
15 Jun 2015
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Pyruvate Dehydrogenase Kinase 1 Participates in Macrophage Polarization via Regulating Glucose Metabolism
Zheng Tan, Na Xie, Huachun Cui, Douglas R. Moellering, Edward Abraham, Victor J. Thannickal, Gang Liu
The Journal of Immunology June 15, 2015, 194 (12) 6082-6089; DOI: 10.4049/jimmunol.1402469

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Pyruvate Dehydrogenase Kinase 1 Participates in Macrophage Polarization via Regulating Glucose Metabolism
Zheng Tan, Na Xie, Huachun Cui, Douglas R. Moellering, Edward Abraham, Victor J. Thannickal, Gang Liu
The Journal of Immunology June 15, 2015, 194 (12) 6082-6089; DOI: 10.4049/jimmunol.1402469
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