title: Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism.
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.
authors.affiliation: 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;
authors.forename: Zheng
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Na
authors.initials: N
authors.lastname: Xie
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Huachun
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294; and.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Moellering
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157.
authors.forename: Edward
authors.initials: E
authors.lastname: Abraham
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; gliu@uab.edu.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
mesh_terms: D000818:Animals; D001419:Bacteria / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D005227:Fatty Acids; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D008070:Lipopolysaccharides; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051195:Toll-Like Receptor 2; D017346:Protein Serine-Threonine Kinases; D005947:Glucose