title: Pro-inflammatory Macrophages Sustain Pyruvate Oxidation through Pyruvate Dehydrogenase for the Synthesis of Itaconate and to Enable Cytokine Expression.
abstract: Upon stimulation with Th1 cytokines or bacterial lipopolysaccharides, resting macrophages shift their phenotype toward a pro-inflammatory state as part of the innate immune response. LPS-activated macrophages undergo profound metabolic changes to adapt to these new physiological requirements. One key step to mediate this metabolic adaptation is the stabilization of HIF1α, which leads to increased glycolysis and lactate release, as well as decreased oxygen consumption. HIF1 abundance can result in the induction of the gene encoding pyruvate dehydrogenase kinase 1 (PDK1), which inhibits pyruvate dehydrogenase (PDH) via phosphorylation. Therefore, it has been speculated that pyruvate oxidation through PDH is decreased in pro-inflammatory macrophages. However, to answer this open question, an in-depth analysis of this metabolic branching point was so far lacking. In this work, we applied stable isotope-assisted metabolomics techniques and demonstrate that pyruvate oxidation is maintained in mature pro-inflammatory macrophages. Glucose-derived pyruvate is oxidized via PDH to generate citrate in the mitochondria. Citrate is used for the synthesis of the antimicrobial metabolite itaconate and for lipogenesis. An increased demand for these metabolites decreases citrate oxidation through the tricarboxylic acid cycle, whereas increased glutamine uptake serves to replenish the TCA cycle. Furthermore, we found that the PDH flux is maintained by unchanged PDK1 abundance, despite the presence of HIF1. By pharmacological intervention, we demonstrate that the PDH flux is an important node for M(LPS) macrophage activation. Therefore, PDH represents a metabolic intervention point that might become a research target for translational medicine to treat chronic inflammatory diseases.
authors.affiliation: From the Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6 Avenue de Swing, L-4367 Belvaux, Luxembourg.
authors.forename: Johannes
authors.initials: J
authors.lastname: Meiser
authors.affiliation: From the Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6 Avenue de Swing, L-4367 Belvaux, Luxembourg.
authors.forename: Lisa
authors.initials: L
authors.lastname: Krämer
authors.affiliation: From the Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6 Avenue de Swing, L-4367 Belvaux, Luxembourg.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Sapcariu
authors.affiliation: From the Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6 Avenue de Swing, L-4367 Belvaux, Luxembourg.
authors.forename: Nadia
authors.initials: N
authors.lastname: Battello
authors.affiliation: From the Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6 Avenue de Swing, L-4367 Belvaux, Luxembourg.
authors.forename: Jenny
authors.initials: J
authors.lastname: Ghelfi
authors.affiliation: From the Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6 Avenue de Swing, L-4367 Belvaux, Luxembourg.
authors.forename: Aymeric Fouquier
authors.initials: AF
authors.lastname: D'Herouel
authors.affiliation: From the Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6 Avenue de Swing, L-4367 Belvaux, Luxembourg.
authors.forename: Alexander
authors.initials: A
authors.lastname: Skupin
authors.affiliation: From the Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6 Avenue de Swing, L-4367 Belvaux, Luxembourg karsten.hiller@uni.lu.
authors.forename: Karsten
authors.initials: K
authors.lastname: Hiller
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D015846:Monokines / Q000096:biosynthesis*; D010084:Oxidation-Reduction / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism*; D013386:Succinates / Q000378:metabolism*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; D015846:Monokines; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D013386:Succinates; D019289:Pyruvic Acid; D017346:Protein Serine-Threonine Kinases; C005229:itaconic acid
keywords: Itaconate; immunology; inflammation; macrophage; metabolic regulation; metabolism; mitochondrial metabolism; pyruvate;