The Monocarboxylate Transporter 4 Is Required for Glycolytic Reprogramming and Inflammatory Response in Macrophages*
- Zheng Tan‡,§,
- Na Xie‡,
- Sami Banerjee‡,
- Huachun Cui‡,
- Mingui Fu¶,
- Victor J. Thannickal‡ and
- Gang Liu‡1
- 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
- the ¶Department of Basic Medical Science, University of Missouri Kansas City, Kansas City, Missouri 64108
- ↵1 To whom correspondence should be addressed: Gang Liu, M.D., Ph.D., Associate Professor, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, 901 19th St. So., BMR II 233, Birmingham, AL 35294. Tel: 205-975-8932, Fax: 205-934-7437; E-mail: gliu{at}uab.edu
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.
Footnotes
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↵* This work was supported, in whole or in part, by National Institutes of Health Grants HL105473 and HL076206 (to G. L.) and HL114470 (to V. J. T.).
- Received August 13, 2014.
- Revision received November 2, 2014.
- © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
