The Monocarboxylate Transporter 4 Is Required for Glycolytic Reprogramming and Inflammatory Response in Macrophages

• Published in: The Journal of biological chemistry 2015-01, Vol.290 (1), p.46-55
• Main Authors: Tan, Zheng, Xie, Na, Banerjee, Sami, Cui, Huachun, Fu, Mingui, Thannickal, Victor J., Liu, Gang
• Format: Article
• Language: English
• Subjects: Animals; Biological Transport; Feedback, Physiological; Gene Expression Regulation; Glycolysis; Glycolysis - genetics; Glycolysis - immunology; Hexokinase - genetics; Hexokinase - immunology; Humans; Immunity, Innate; Immunology; Inflammation; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Inflammation - pathology; Lactic Acid - metabolism; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Lipopolysaccharide (LPS); Lipopolysaccharides - pharmacology; Macrophage; Macrophage Activation - drug effects; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Macrophages, Alveolar - drug effects; Macrophages, Alveolar - immunology; Macrophages, Alveolar - metabolism; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; MCT4; Mice; Mice, Inbred C57BL; Monocarboxylic Acid Transporters - genetics; Monocarboxylic Acid Transporters - immunology; Monocarboxylic Acid Transporters - metabolism; Muscle Proteins - genetics; Muscle Proteins - immunology; Muscle Proteins - metabolism; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - immunology; Phosphofructokinase-2 - genetics; Phosphofructokinase-2 - immunology; Primary Cell Culture; Signal Transduction; Toll-like Receptor (TLR); Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - immunology; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.603589

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.Glycolysis has an important role in inflammation. MCT4 is up-regulated in inflammatorily activated macrophages and required for innate immune response. MCT4 up-regulation represents a positive feedback mechanism in inflammation. Delineation of the role of MCT4 provides further insight into the regulation of inflammation by glycolysis.