title: PHD2 Is a Regulator for Glycolytic Reprogramming in Macrophages.
abstract: The prolyl-4-hydroxylase domain (PHD) enzymes are regarded as the molecular oxygen sensors. There is an interplay between oxygen availability and cellular metabolism, which in turn has significant effects on the functionality of innate immune cells, such as macrophages. However, if and how PHD enzymes affect macrophage metabolism are enigmatic. We hypothesized that macrophage metabolism and function can be controlled via manipulation of PHD2. We characterized the metabolic phenotypes of PHD2-deficient RAW cells and primary PHD2 knockout bone marrow-derived macrophages (BMDM). Both showed typical features of anaerobic glycolysis, which were paralleled by increased pyruvate dehydrogenase kinase 1 (PDK1) protein levels and a decreased pyruvate dehydrogenase enzyme activity. Metabolic alterations were associated with an impaired cellular functionality. Inhibition of PDK1 or knockout of hypoxia-inducible factor 1α (HIF-1α) reversed the metabolic phenotype and impaired the functionality of the PHD2-deficient RAW cells and BMDM. Taking these results together, we identified a critical role of PHD2 for a reversible glycolytic reprogramming in macrophages with a direct impact on their function. We suggest that PHD2 serves as an adjustable switch to control macrophage behavior.
authors: Institute for Cardiovascular Physiology, Georg August University Göttingen, Göttingen, Germany.
authors: Annemarie
authors: A
authors: Guentsch
authors: Institute for Cardiovascular Physiology, Georg August University Göttingen, Göttingen, Germany.
authors: Angelika
authors: A
authors: Beneke
authors: Institute for Cardiovascular Physiology, Georg August University Göttingen, Göttingen, Germany.
authors: Lija
authors: L
authors: Swain
authors: Institute for Cardiovascular Physiology, Georg August University Göttingen, Göttingen, Germany.
authors: Katja
authors: K
authors: Farhat
authors: Institute for Cardiovascular Physiology, Georg August University Göttingen, Göttingen, Germany.
authors: Shunmugam
authors: S
authors: Nagarajan
authors: Department of Clinical Pathobiochemistry, Institute of Clinical Chemistry and Laboratory Medicine, Technical University Dresden, Dresden, Germany.
authors: Ben
authors: B
authors: Wielockx
authors: Microarray and Deep-Sequencing Core Facility, University Medical Center Göttingen, Göttingen, Germany.
authors: Kaamini
authors: K
authors: Raithatha
authors: Institute for Cellular Biochemistry, Georg August University Göttingen, Göttingen, Germany.
authors: Jan
authors: J
authors: Dudek
authors: Institute for Cellular Biochemistry, Georg August University Göttingen, Göttingen, Germany.
authors: Peter
authors: P
authors: Rehling
authors: Institute for Cardiovascular Physiology, Georg August University Göttingen, Göttingen, Germany.
authors: Anke
authors: A
authors: Zieseniss
authors: Institute for Cardiovascular Physiology, Georg August University Göttingen, Göttingen, Germany.
authors: Aline
authors: A
authors: Jatho
authors: Department of Cardiology, King's College London British Heart Foundation Centre, London, United Kingdom.
authors: Mei
authors: M
authors: Chong
authors: Department of Cardiology, King's College London British Heart Foundation Centre, London, United Kingdom.
authors: Celio X C
authors: CXC
authors: Santos
authors: Department of Cardiology, King's College London British Heart Foundation Centre, London, United Kingdom.
authors: Ajay M
authors: AM
authors: Shah
authors: Institute for Cardiovascular Physiology, Georg August University Göttingen, Göttingen, Germany doerthe.katschinski@med.uni-goettingen.de.
authors: Dörthe M
authors: DM
authors: Katschinski
mesh_terms: D000818:Animals; D002460:Cell Line; D065150:Cellular Reprogramming; D055786:Gene Knockout Techniques; D006019:Glycolysis; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D000067996:RAW 264.7 Cells; D015398:Signal Transduction
chemical_list: C490190:EGLN1 protein, human; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: PDK; dioxygenases; hypoxia; macrophages; prolyl-4-hydroxylase domain