title: The monocarboxylate transporter 4 is required for glycolytic reprogramming and inflammatory response in macrophages.
abstract: There has been fast growing evidence showing that glycolysis plays a critical role in the activation of immune cells. Enhanced glycolysis leads to increased formation of intracellular lactate that is exported to the extracellular environment by monocarboxylate transporter 4 (MCT4). Although the biological activities of extracellular lactate have been well studied, it is less understood how the lactate export is regulated or whether lactate export affects glycolysis during inflammatory activation. In this study, we found that MCT4 is up-regulated by TLR2 and TLR4, but not TLR3 agonists in a variety of macrophages. The increased expression of MCT4 was mediated by MYD88 in a NF-κB-dependent manner. Furthermore, we found that MCT4 is required for macrophage activation upon TLR2 and TLR4 stimulations, as evidenced by attenuated expression of proinflammatory mediators in macrophages with MCT4 knockdown. Mechanistically, we found that MCT4 knockdown leads to enhanced intracellular accumulation of lactate and decreased glycolysis in LPS-treated macrophages. We found that LPS-induced expression of key glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 is diminished in macrophages with MCT4 knockdown. Our data suggest that MCT4 up-regulation represents a positive feedback mechanism in macrophages to maintain a high glycolytic rate that is essential to a fully activated inflammatory response.
authors.affiliation: From the Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, the Department of Immunology, School of Basic Medicine, Tongji Medical College, HuaZhong University of Science and Technology, 430030 Wuhan, China, and.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Tan
authors.affiliation: From the Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Na
authors.initials: N
authors.lastname: Xie
authors.affiliation: From the Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Sami
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: From the Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Huachun
authors.initials: H
authors.lastname: Cui
authors.affiliation: the Department of Basic Medical Science, University of Missouri Kansas City, Kansas City, Missouri 64108.
authors.forename: Mingui
authors.initials: M
authors.lastname: Fu
authors.affiliation: From the Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.affiliation: From the Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, gliu@uab.edu.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
mesh_terms: D000818:Animals; D001692:Biological Transport; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006019:Glycolysis / Q000235:genetics* / Q000276:immunology; D006593:Hexokinase / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019344:Lactic Acid / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D027501:Monocarboxylic Acid Transporters / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D025481:Phosphofructokinase-2 / Q000235:genetics / Q000276:immunology; D061251:Primary Cell Culture; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology
chemical_list: D008070:Lipopolysaccharides; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C406962:SLC16A4 protein, human; C498648:Slc16a4 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D019344:Lactic Acid; D006593:Hexokinase; D025481:Phosphofructokinase-2
keywords: Glycolysis; Inflammation; Lipopolysaccharide (LPS); MCT4; Macrophage; Toll-like Receptor (TLR)