Guentsch Annemarie, Beneke Angelika, Swain Lija, Farhat Katja, Nagarajan Shunmugam, Wielockx Ben, Raithatha Kaamini, Dudek Jan, Rehling Peter, Zieseniss Anke, Jatho Aline, Chong Mei, Santos Celio X C, Shah Ajay M, Katschinski Dörthe M
Institute for Cardiovascular Physiology, Georg August University Göttingen, Göttingen, Germany.
Department of Clinical Pathobiochemistry, Institute of Clinical Chemistry and Laboratory Medicine, Technical University Dresden, Dresden, Germany.
Mol Cell Biol. 2016 Dec 19;37(1). doi: 10.1128/MCB.00236-16. Print 2017 Jan 1.
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.
脯氨酰-4-羟化酶结构域（PHD）酶被视为分子氧传感器。氧的可利用性与细胞代谢之间存在相互作用，这反过来又对先天免疫细胞（如巨噬细胞）的功能产生重大影响。然而，PHD酶是否以及如何影响巨噬细胞代谢仍不清楚。我们假设巨噬细胞的代谢和功能可以通过对PHD2的操控来控制。我们对缺乏PHD2的RAW细胞和原发性PHD2基因敲除的骨髓来源巨噬细胞（BMDM）的代谢表型进行了表征。两者均表现出无氧糖酵解的典型特征，同时丙酮酸脱氢酶激酶1（PDK1）蛋白水平升高，丙酮酸脱氢酶活性降低。代谢改变与细胞功能受损有关。抑制PDK1或敲除缺氧诱导因子1α（HIF-1α）可逆转代谢表型，并损害缺乏PHD2的RAW细胞和BMDM的功能。综合这些结果，我们确定了PHD2在巨噬细胞中可逆性糖酵解重编程中的关键作用，这对其功能有直接影响。我们认为PHD2作为一个可调节的开关来控制巨噬细胞的行为。
