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The oxygen sensor PHD2 affects energy metabolism and cell function in macrophages

dc.contributor.advisorKatschinski, Dörthe Prof. Dr.
dc.contributor.authorGüntsch, Annemarie
dc.date.accessioned2016-11-08T09:22:53Z
dc.date.available2016-11-08T09:22:53Z
dc.date.issued2016-11-08
dc.identifier.urihttp://hdl.handle.net/11858/00-1735-0000-002B-7C93-8
dc.identifier.urihttp://dx.doi.org/10.53846/goediss-5941
dc.language.isoengde
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc610
dc.titleThe oxygen sensor PHD2 affects energy metabolism and cell function in macrophagesde
dc.typedoctoralThesisde
dc.contributor.refereeKatschinski, Dörthe Prof. Dr.
dc.date.examination2016-09-23
dc.description.abstractengMacrophages are key players in the innate immune system and contribute significantly to inflammation in ischemic tissues, such as the infarcted heart. During inflammation, macrophages are involved in tissue remodeling, which is needed for the reconstitution of the inflamed organ. Ischemic and inflamed tissues are characterized by a scarcity of oxygen. Macrophages migrate to the site of inflammation against the O2-gradient and therefore have to adapt rapidly to low oxygen concentrations. This adaptation is mediated by the hypoxia inducible factor (HIF)/prolyl-4-hydroxylase domain enzyme (PHD) pathway. The HIF-α subunit is hydroxylated by the three PHDs (PHD1-3) in an oxygen-dependent way. In normoxia, PHD2 has been described to be the main oxygen sensor. In hypoxia, HIF is stabilized and induces a specific gene expression programme. This ensures the survival of the cell in conditions of low oxygen availability. I analyzed the impact of PHD2 on macrophage function using myeloid specific conditional PHD2 knockout mice (PHD2flox/flox x LysMCre+/-) and a stably transduced RAW264.7 (RAW) macrophage cell line that express a PHD2 shRNA construct resulting in a knockdown of PHD2. In PHD2 deficient RAW cells and bone marrow derived macrophages (BMDMs), a normoxic stabilization of HIF-1α was observed. The expression of the HIF target genes such as pyruvate dehydrogenase kinase 1 (PDK1) was increased in PHD2 deficient macrophages compared to wt cells under normoxic conditions. PDK1 is an important mediator of the metabolic adaptation during hypoxia and stimulates the shift to anaerobic glycolysis. Increased expression of PDK1 resulted in metabolic reprogramming in PHD2 deficient macrophages which was shown by increased lactate levels and decreased ATP levels. Compared to wildtype macrophages, PHD2 deficient macrophages demonstrated decreased oxygen consumption rates and increased glycolysis. The observed glycolytic phenotype was associated with an impaired migration and phagocytosis. The glycolytic phenotype and the defect in migration and phagocytosis were partially reversed by pharmacological inhibition of PDK using dichloroacetate (DCA). In summary, my data suggest that PHD2 plays an important role in macrophage function by modulating cellular metabolism through PDK1.de
dc.contributor.coRefereeAlves, Frauke Prof. Dr.
dc.subject.engPHD2de
dc.subject.enghypoxiade
dc.subject.engmacrophagesde
dc.subject.engpdk1de
dc.identifier.urnurn:nbn:de:gbv:7-11858/00-1735-0000-002B-7C93-8-4
dc.affiliation.instituteMedizinische Fakultät
dc.subject.gokfullMedizin (PPN619874732)de
dc.identifier.ppn872117618


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