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  1. Article ; Online: Loss of PHD3 in myeloid cells dampens the inflammatory response and fibrosis after hind-limb ischemia.

    Beneke, Angelika / Guentsch, Annemarie / Hillemann, Annette / Zieseniss, Anke / Swain, Lija / Katschinski, Dörthe M

    Cell death & disease

    2017  Volume 8, Issue 8, Page(s) e2976

    Abstract: Macrophages are essential for the inflammatory response after an ischemic insult and thereby influence tissue recovery. For the oxygen sensing prolyl-4-hydroxylase domain enzyme (PHD) 2 a clear impact on the macrophage-mediated arteriogenic response ... ...

    Abstract Macrophages are essential for the inflammatory response after an ischemic insult and thereby influence tissue recovery. For the oxygen sensing prolyl-4-hydroxylase domain enzyme (PHD) 2 a clear impact on the macrophage-mediated arteriogenic response after hind-limb ischemia has been demonstrated previously, which involves fine tuning a M2-like macrophage population. To analyze the role of PHD3 in macrophages, we performed hind-limb ischemia (ligation and excision of the femoral artery) in myeloid-specific PHD3 knockout mice (PHD3
    MeSH term(s) Animals ; Cytochrome P-450 Enzyme System/genetics ; Cytochrome P-450 Enzyme System/metabolism ; Disease Models, Animal ; Fibrosis/enzymology ; Fibrosis/metabolism ; Fibrosis/physiopathology ; Hindlimb ; Hypoxia-Inducible Factor-Proline Dioxygenases/genetics ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism ; Inflammation/enzymology ; Inflammation/metabolism ; Inflammation/physiopathology ; Ischemia/enzymology ; Ischemia/metabolism ; Ischemia/physiopathology ; Macrophages/metabolism ; Mice ; Mice, Knockout
    Chemical Substances Cytochrome P-450 Enzyme System (9035-51-2) ; EGLN3 protein, human (EC 1.14.11.29) ; Hypoxia-Inducible Factor-Proline Dioxygenases (EC 1.14.11.29) ; Cyp2s1 protein, mouse (EC 1.14.14.1)
    Language English
    Publishing date 2017--10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/cddis.2017.375
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Mucosal inflammation downregulates PHD1 expression promoting a barrier-protective HIF-1α response in ulcerative colitis patients.

    Brown, Eric / Rowan, Catherine / Strowitzki, Moritz J / Fagundes, Raphael R / Faber, Klaas Nico / Güntsch, Annemarie / Halligan, Doug N / Kugler, Julia / Jones, Fiona / Lee, Chee T / Doherty, Glen / Taylor, Cormac T

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology

    2020  Volume 34, Issue 3, Page(s) 3732–3742

    Abstract: The HIF hydroxylase enzymes (PHD1-3 and FIH) are cellular oxygen-sensors which confer hypoxic-sensitivity upon the hypoxia-inducible factors HIF-1α and HIF-2α. Microenvironmental hypoxia has a strong influence on the epithelial and immune cell function ... ...

    Abstract The HIF hydroxylase enzymes (PHD1-3 and FIH) are cellular oxygen-sensors which confer hypoxic-sensitivity upon the hypoxia-inducible factors HIF-1α and HIF-2α. Microenvironmental hypoxia has a strong influence on the epithelial and immune cell function through HIF-dependent gene expression and consequently impacts upon the course of disease progression in ulcerative colitis (UC), with HIF-1α being protective while HIF-2α promotes disease. However, little is known about how inflammation regulates hypoxia-responsive pathways in UC patients. Here we demonstrate that hypoxia is a prominent microenvironmental feature of the mucosa in UC patients with active inflammatory disease. Furthermore, we found that inflammation drives transcriptional programming of the HIF pathway including downregulation of PHD1 thereby increasing the tissue responsiveness to hypoxia and skewing this response toward protective HIF-1 over detrimental HIF-2 activation. We identified CEBPα as a transcriptional regulator of PHD1 mRNA expression which is downregulated in both inflamed tissue derived from patients and in cultured intestinal epithelial cells treated with inflammatory cytokines. In summary, we propose that PHD1 downregulation skews the hypoxic response toward enhanced protective HIF-1α stabilization in the inflamed mucosa of UC patients.
    MeSH term(s) Blotting, Western ; Caco-2 Cells ; Chromatin Immunoprecipitation ; Colitis, Ulcerative/genetics ; Colitis, Ulcerative/metabolism ; Computational Biology ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Hypoxia-Inducible Factor-Proline Dioxygenases/genetics ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism ; Immunohistochemistry ; Inflammation/genetics ; Inflammation/metabolism ; Inflammatory Bowel Diseases/genetics ; Inflammatory Bowel Diseases/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
    Chemical Substances HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; RNA, Messenger ; EGLN2 protein, human (EC 1.14.11.29) ; Hypoxia-Inducible Factor-Proline Dioxygenases (EC 1.14.11.29)
    Language English
    Publishing date 2020-01-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    DOI 10.1096/fj.201902103R
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Book ; Online ; Thesis: The oxygen sensor PHD2 affects energy metabolism and cell function in macrophages

    Güntsch, Annemarie [Verfasser] / Katschinski, Dörthe [Akademischer Betreuer] [Gutachter] / Alves, Frauke [Gutachter]

    2016  

    Author's details Annemarie Güntsch ; Gutachter: Dörthe Katschinski, Frauke Alves ; Betreuer: Dörthe Katschinski
    Keywords Medizin, Gesundheit ; Medicine, Health
    Subject code sg610
    Language English
    Publisher Niedersächsische Staats- und Universitätsbibliothek Göttingen
    Publishing place Göttingen
    Document type Book ; Online ; Thesis
    Database Digital theses on the web

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  4. Article ; Online: PHD2 Is a Regulator for Glycolytic Reprogramming in Macrophages

    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.

    Molecular and Cellular Biology. 2017 Jan. 1, v. 37, no. 1 p.e00236-16-

    2017  

    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 ...

    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.
    Keywords enzyme activity ; glycolysis ; macrophages ; oxygen ; phenotype ; pyruvate dehydrogenase (acetyl-transferring) kinase ; pyruvate dehydrogenase (lipoamide) ; PDK ; prolyl-4-hydroxylase domain ; dioxygenases ; hypoxia
    Language English
    Dates of publication 2017-0101
    Publishing place Taylor & Francis
    Document type Article ; Online
    ZDB-ID 779397-2
    ISSN 1098-5549 ; 0270-7306
    ISSN (online) 1098-5549
    ISSN 0270-7306
    DOI 10.1128/MCB.00236-16
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: PHD2 Is a Regulator for Glycolytic Reprogramming in Macrophages.

    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

    Molecular and cellular biology

    2016  Volume 37, Issue 1

    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 ...

    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.
    MeSH term(s) Animals ; Cell Line ; Cellular Reprogramming ; Gene Knockout Techniques ; Glycolysis ; Humans ; Hypoxia-Inducible Factor-Proline Dioxygenases/genetics ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism ; Macrophages/cytology ; Macrophages/metabolism ; Mice ; RAW 264.7 Cells ; Signal Transduction
    Chemical Substances EGLN1 protein, human (EC 1.14.11.2) ; Egln1 protein, mouse (EC 1.14.11.29) ; Hypoxia-Inducible Factor-Proline Dioxygenases (EC 1.14.11.29)
    Language English
    Publishing date 2016-12-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 779397-2
    ISSN 1098-5549 ; 0270-7306
    ISSN (online) 1098-5549
    ISSN 0270-7306
    DOI 10.1128/MCB.00236-16
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Redox Imaging Using Cardiac Myocyte-Specific Transgenic Biosensor Mice.

    Swain, Lija / Kesemeyer, Andrea / Meyer-Roxlau, Stefanie / Vettel, Christiane / Zieseniss, Anke / Güntsch, Annemarie / Jatho, Aline / Becker, Andreas / Nanadikar, Maithily S / Morgan, Bruce / Dennerlein, Sven / Shah, Ajay M / El-Armouche, Ali / Nikolaev, Viacheslav O / Katschinski, Dörthe M

    Circulation research

    2016  Volume 119, Issue 9, Page(s) 1004–1016

    Abstract: Rationale: Changes in redox potentials of cardiac myocytes are linked to several cardiovascular diseases. Redox alterations are currently mostly described qualitatively using chemical sensors, which however do not allow quantifying redox potentials, ... ...

    Abstract Rationale: Changes in redox potentials of cardiac myocytes are linked to several cardiovascular diseases. Redox alterations are currently mostly described qualitatively using chemical sensors, which however do not allow quantifying redox potentials, lack specificity, and the possibility to analyze subcellular domains. Recent advances to quantitatively describe defined redox changes include the application of genetically encoded redox biosensors.
    Objective: Establishment of mouse models, which allow the quantification of the glutathione redox potential (E
    Methods and results: We generated transgenic mice with cardiac myocyte-restricted expression of Grx1-roGFP2 targeted either to the mitochondrial matrix or to the cytoplasm. The response of the roGFP2 toward H
    Conclusions: We introduce redox biosensor mice as a new tool, which allows quantification of defined alterations of E
    MeSH term(s) Animals ; Biosensing Techniques/methods ; Cells, Cultured ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; Heart/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myocytes, Cardiac/metabolism ; Organ Culture Techniques ; Oxidation-Reduction ; Oxygen Consumption/physiology
    Chemical Substances Green Fluorescent Proteins (147336-22-9)
    Language English
    Publishing date 2016-08-23
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80100-8
    ISSN 1524-4571 ; 0009-7330 ; 0931-6876
    ISSN (online) 1524-4571
    ISSN 0009-7330 ; 0931-6876
    DOI 10.1161/CIRCRESAHA.116.309551
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Populational equilibrium through exosome-mediated Wnt signaling in tumor progression of diffuse large B-cell lymphoma.

    Koch, Raphael / Demant, Martin / Aung, Thiha / Diering, Nina / Cicholas, Anna / Chapuy, Bjoern / Wenzel, Dirk / Lahmann, Marlen / Güntsch, Annemarie / Kiecke, Christina / Becker, Sabrina / Hupfeld, Timo / Venkataramani, Vivek / Ziepert, Marita / Opitz, Lennart / Klapper, Wolfram / Trümper, Lorenz / Wulf, Gerald G

    Blood

    2014  Volume 123, Issue 14, Page(s) 2189–2198

    Abstract: Tumors are composed of phenotypically heterogeneous cell populations. The nongenomic mechanisms underlying transitions and interactions between cell populations are largely unknown. Here, we show that diffuse large B-cell lymphomas possess a self- ... ...

    Abstract Tumors are composed of phenotypically heterogeneous cell populations. The nongenomic mechanisms underlying transitions and interactions between cell populations are largely unknown. Here, we show that diffuse large B-cell lymphomas possess a self-organized infrastructure comprising side population (SP) and non-SP cells, where transitions between clonogenic states are modulated by exosome-mediated Wnt signaling. DNA methylation modulated SP-non-SP transitions and was correlated with the reciprocal expressions of Wnt signaling pathway agonist Wnt3a in SP cells and the antagonist secreted frizzled-related protein 4 in non-SP cells. Lymphoma SP cells exhibited autonomous clonogenicity and exported Wnt3a via exosomes to neighboring cells, thus modulating population equilibrium in the tumor.
    MeSH term(s) Cell Count ; Cell Proliferation ; Clone Cells/pathology ; Disease Progression ; Exosomes/physiology ; HEK293 Cells ; Homeostasis/physiology ; Humans ; Lymphoma, Large B-Cell, Diffuse/metabolism ; Lymphoma, Large B-Cell, Diffuse/pathology ; Neoplastic Stem Cells/pathology ; Protein Transport ; Tumor Cells, Cultured ; Wnt Signaling Pathway/physiology
    Language English
    Publishing date 2014-02-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood-2013-08-523886
    Database MEDical Literature Analysis and Retrieval System OnLINE

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