Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype

Byong Keol Min, Sungmi Park, Hyeon Ji Kang, Dong Wook Kim, Hye Jin Ham, Chae Myeong Ha, Byung Jun Choi, Jung Yi Lee, Chang Joo Oh, Eun Kyung Yoo, Hui Eon Kim, Byung Gyu Kim, Jae Han Jeon, Do Young Hyeon, Daehee Hwang, Yong Hoon Kim, Chul Ho Lee, Taeho Lee, Jung Whan Kim, Yeon Kyung ChoiKeun Gyu Park, Ajay Chawla, Jongsoon Lee, Robert Harris, In Kyu Lee

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.

Original languageEnglish (US)
Number of pages1
JournalFrontiers in immunology
Volume10
DOIs
StatePublished - Jan 1 2019

Fingerprint

Macrophages
Phenotype
Pyruvic Acid
Insulin Resistance
Obesity
Pharmacology
Acetyl Coenzyme A
High Fat Diet
Myeloid Cells
Lipopolysaccharides
Adipose Tissue
Oxidoreductases
Respiration
Transplantation
Bone Marrow
Inflammation
pyruvate dehydrogenase (acetyl-transferring) kinase
Health
Therapeutics

Keywords

  • dichloroacetate
  • high-fat diet
  • inflammation
  • insulin resistance
  • macrophage polarization
  • metabolic reprogramming
  • pyruvate dehydrogenase kinase

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype. / Min, Byong Keol; Park, Sungmi; Kang, Hyeon Ji; Kim, Dong Wook; Ham, Hye Jin; Ha, Chae Myeong; Choi, Byung Jun; Lee, Jung Yi; Oh, Chang Joo; Yoo, Eun Kyung; Kim, Hui Eon; Kim, Byung Gyu; Jeon, Jae Han; Hyeon, Do Young; Hwang, Daehee; Kim, Yong Hoon; Lee, Chul Ho; Lee, Taeho; Kim, Jung Whan; Choi, Yeon Kyung; Park, Keun Gyu; Chawla, Ajay; Lee, Jongsoon; Harris, Robert; Lee, In Kyu.

In: Frontiers in immunology, Vol. 10, 01.01.2019.

Research output: Contribution to journalArticle

Min, BK, Park, S, Kang, HJ, Kim, DW, Ham, HJ, Ha, CM, Choi, BJ, Lee, JY, Oh, CJ, Yoo, EK, Kim, HE, Kim, BG, Jeon, JH, Hyeon, DY, Hwang, D, Kim, YH, Lee, CH, Lee, T, Kim, JW, Choi, YK, Park, KG, Chawla, A, Lee, J, Harris, R & Lee, IK 2019, 'Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype', Frontiers in immunology, vol. 10. https://doi.org/10.3389/fimmu.2019.00944
Min, Byong Keol ; Park, Sungmi ; Kang, Hyeon Ji ; Kim, Dong Wook ; Ham, Hye Jin ; Ha, Chae Myeong ; Choi, Byung Jun ; Lee, Jung Yi ; Oh, Chang Joo ; Yoo, Eun Kyung ; Kim, Hui Eon ; Kim, Byung Gyu ; Jeon, Jae Han ; Hyeon, Do Young ; Hwang, Daehee ; Kim, Yong Hoon ; Lee, Chul Ho ; Lee, Taeho ; Kim, Jung Whan ; Choi, Yeon Kyung ; Park, Keun Gyu ; Chawla, Ajay ; Lee, Jongsoon ; Harris, Robert ; Lee, In Kyu. / Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype. In: Frontiers in immunology. 2019 ; Vol. 10.
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AU - Kang, Hyeon Ji

AU - Kim, Dong Wook

AU - Ham, Hye Jin

AU - Ha, Chae Myeong

AU - Choi, Byung Jun

AU - Lee, Jung Yi

AU - Oh, Chang Joo

AU - Yoo, Eun Kyung

AU - Kim, Hui Eon

AU - Kim, Byung Gyu

AU - Jeon, Jae Han

AU - Hyeon, Do Young

AU - Hwang, Daehee

AU - Kim, Yong Hoon

AU - Lee, Chul Ho

AU - Lee, Taeho

AU - Kim, Jung Whan

AU - Choi, Yeon Kyung

AU - Park, Keun Gyu

AU - Chawla, Ajay

AU - Lee, Jongsoon

AU - Harris, Robert

AU - Lee, In Kyu

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N2 - Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.

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KW - inflammation

KW - insulin resistance

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