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

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.

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

“…Knockdown of PDK1 in murine BMDMs suppressed M1 by attenuating glycolytic flux, the expression of pro.inflammatory cytokines (TNF-α and IL-6) and consequently aerobic glycolysis, but enhanced M2 activation by mitochondrial respiration [220]. Moreover, combined deletion of two forms of pyruvate dehydrogenase kinase PDK2 and PDK4 in myeloid cells prevents M1 polarization and correlates with the improved mitochondrial respiration in mouse models [221]. Similarly, PDK1 was identified as a HIF-1α target gene, and HIF-1α-PDK1 axis induced active glycolysis with up-regulation of glycolytic genes, such as GLUT1, phosphoglycerate kinase 1 (PGK1) or lactate dehydrogenase A (LDHA) [222].…”

The Interplay Between Tissue Niche and Macrophage Cellular Metabolism in Obesity

“…Pyruvate dehydrogenase kinase (PDK) has been postulated to be important for M1 polarization as it reduces entry of carbons from glycolysis into the TCA cycle by inhibiting pyruvate dehydrogenase (PHD). Indeed, pharmacological inhibition of PDK2 and−4 blocks inflammatory activation of cultured macrophages (146). Myeloid-specific ablation of PDK2/4 using a bone-marrow transplant approach led to reduced weight gain, improved glucose tolerance and reduced adiposity and liver fat when fed a HFD.…”

Fursultiamine Alleviates Choroidal Neovascularization by Suppressing Inflammation and Metabolic Reprogramming

“… 40 This immunometabolic disease mechanism was supported by a recent study, which demonstrated that both genetic and pharmacological inhibition of mitochondrial PDH kinase isozymes improves mitochondrial function and decreases expression of proinflammatory cytokines. 41 Taken together, our data suggest that fursultiamine disrupted metabolic reprogramming from OXPHOS to aerobic glycolysis, which could be associated with the attenuated inflammatory response in the RPE.…”