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.