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51. Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation

Author

Künzel, Stephan R., primary, Hoffmann, Maximilian, additional, Weber, Silvio, additional, Künzel, Karolina, additional, Kämmerer, Susanne, additional, Günscht, Mario, additional, Klapproth, Erik, additional, Rausch, Johanna S.E., additional, Sadek, Mirna S., additional, Kolanowski, Tomasz, additional, Meyer-Roxlau, Stefanie, additional, Piorkowski, Christopher, additional, Tugtekin, Sems M., additional, Rose-John, Stefan, additional, Yin, Xiaoke, additional, Mayr, Manuel, additional, Kuhlmann, Jan Dominik, additional, Wimberger, Pauline, additional, Grützmann, Konrad, additional, Herzog, Natalie, additional, Küpper, Jan-Heiner, additional, O’Reilly, Molly, additional, Kabir, S. Nashitha, additional, Sommerfeld, Laura C., additional, Guan, Kaomei, additional, Wielockx, Ben, additional, Fabritz, Larissa, additional, Nattel, Stanley, additional, Ravens, Ursula, additional, Dobrev, Dobromir, additional, Wagner, Michael, additional, and El-Armouche, Ali, additional

Published
2021
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52. HIF2α regulates the synthesis and release of epinephrine in the adrenal medulla

Author

Watts, Deepika, primary, Bechmann, Nicole, additional, Meneses, Ana, additional, Poutakidou, Ioanna K., additional, Kaden, Denise, additional, Conrad, Catleen, additional, Krüger, Anja, additional, Stein, Johanna, additional, El-Armouche, Ali, additional, Chavakis, Triantafyllos, additional, Eisenhofer, Graeme, additional, Peitzsch, Mirko, additional, and Wielockx, Ben, additional

Published
2021
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54. HIF2α is a direct regulator of neutrophil motility

Author

Sormendi, Sundary, primary, Deygas, Mathieu, additional, Sinha, Anupam, additional, Bernard, Mathilde, additional, Krüger, Anja, additional, Kourtzelis, Ioannis, additional, Le Lay, Gregoire, additional, Sáez, Pablo J., additional, Gerlach, Michael, additional, Franke, Kristin, additional, Meneses, Ana, additional, Kräter, Martin, additional, Palladini, Alessandra, additional, Guck, Jochen, additional, Coskun, Ünal, additional, Chavakis, Triantafyllos, additional, Vargas, Pablo, additional, and Wielockx, Ben, additional

Published
2021
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55. The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases

Author

Gorodetska, Ielizaveta, primary, Offermann, Anna, additional, Pueschel, Jakob, additional, Lukiyanchuk, Vasyl, additional, Gaete, Diana, additional, Kurzyukova, Anastasia, additional, Labitzky, Vera, additional, Schwarz, Franziska, additional, Lange, Tobias, additional, Knopf, Franziska, additional, Wielockx, Ben, additional, Krause, Mechthild, additional, Perner, Sven, additional, and Dubrovska, Anna, additional

Published
2021
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60. Mammalian Intracellular Dickkopf1 Couples Proteostasis with Inflammation

Author

Jaschke, Nikolai, primary, Pählig, Sophie, additional, Sinha, Anupam, additional, Adolph, Timon E., additional, Gentzel, Marc, additional, Ledesma-Colunga, Maria, additional, Wang, Andrew, additional, Grzybek, Michal, additional, Thiele, Sylvia, additional, Schwaerzler, Julian, additional, Bozec, Aline, additional, Meng, Xianyi, additional, Groetsch, Bettina, additional, Tilg, Herbert, additional, Wielockx, Ben, additional, Hofbauer, Lorenz C., additional, Rauner, Martina, additional, Göbel, Andy, additional, and Rachner, Tilman D., additional

Published
2021
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61. Short-Term Hypoxia Dampens Inflammation in vivo via Enhanced Adenosine Release and Adenosine 2B Receptor Stimulation

Author

Kiers, Dorien, Wielockx, Ben, Peters, Esther, van Eijk, Lucas T, Gerretsen, Jelle, John, Aaron, Janssen, Emmy, Groeneveld, Rianne, Peters, Mara, Damen, Lars, Meneses, Ana M, Krüger, Anja, Langereis, Jeroen D, Zomer, Aldert L, Blackburn, Michael R, Joosten, Leo A, Netea, Mihai G, Riksen, Niels P, van der Hoeven, Johannes G, Scheffer, Gert-Jan, Eltzschig, Holger K, Pickkers, Peter, Kox, Matthijs, LS Klinisch Onderzoek Wagenaar, dI&I I&I-4, LS Klinisch Onderzoek Wagenaar, and dI&I I&I-4

Subjects
0301 basic medicine, Adenosine, medicine.medical_treatment, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], lcsh:Medicine, Inflammation, Pharmacology, Systemic inflammation, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Endotoxin, medicine, Animals, Humans, Hypoxia, Adenosine 2B receptor, lcsh:R5-920, business.industry, lcsh:R, Receptors, Purinergic P1, Interleukin, Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16], General Medicine, Hypoxia (medical), Purinergic signalling, Hypoxia-Inducible Factor 1, alpha Subunit, Endotoxemia, 3. Good health, Interleukin-10, Up-Regulation, Interleukin 10, Disease Models, Animal, 030104 developmental biology, Cytokine, Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10], Cytokines, medicine.symptom, business, lcsh:Medicine (General), 030217 neurology & neurosurgery, medicine.drug, Research Paper
Abstract

Hypoxia and inflammation are closely intertwined phenomena. Critically ill patients often suffer from systemic inflammatory conditions and concurrently experience short-lived hypoxia. We evaluated the effects of short-term hypoxia on systemic inflammation, and show that it potently attenuates pro-inflammatory cytokine responses during murine endotoxemia. These effects are independent of hypoxia-inducible factors (HIFs), but involve augmented adenosine levels, in turn resulting in an adenosine 2B receptor-mediated post-transcriptional increase of interleukin (IL)-10 production. We translated our findings to humans using the experimental endotoxemia model, where short-term hypoxia resulted in enhanced plasma concentrations of adenosine, augmentation of endotoxin-induced circulating IL-10 levels, and concurrent attenuation of the pro-inflammatory cytokine response. Again, HIFs were shown not to be involved. Taken together, we demonstrate that short-term hypoxia dampens the systemic pro-inflammatory cytokine response through enhanced purinergic signaling in mice and men. These effects may contribute to outcome and provide leads for immunomodulatory treatment strategies for critically ill patients., Highlights • Short-term hypoxia attenuates the systemic pro-inflammatory cytokine response in vivo in both mice and men • The underlying mechanism involves adenosine 2B receptor-mediated enhanced production of anti-inflammatory interleukin-10 • These effects may contribute to outcome and provide leads for novel treatment strategies for critically ill patients Inflammation and short bouts of low oxygen levels are frequently encountered phenomena in severely ill patients admitted to the Intensive Care unit. This study investigated the effect of short-term low oxygen levels on the inflammatory response in both mice and humans. The results show that a short period of low levels of oxygen potently dampens inflammation, and identify the underlying mechanisms. These effects of low oxygen levels may contribute to the outcome of severely ill patients. Furthermore, the increased understanding of the underlying mechanisms provided by this study can be used to develop therapies to dampen inflammation in patients.

Published
2018

63. HIF2α supports pro-metastatic behavior in pheochromocytomas/paragangliomas

Author

Bechmann, Nicole, primary, Moskopp, Mats Leif, additional, Ullrich, Martin, additional, Calsina, Bruna, additional, Wallace, Pål William, additional, Richter, Susan, additional, Friedemann, Markus, additional, Langton, Katharina, additional, Fliedner, Stephanie M J, additional, Timmers, Henri J L M, additional, Nölting, Svenja, additional, Beuschlein, Felix, additional, Fassnacht, Martin, additional, Prejbisz, Aleksander, additional, Pacak, Karel, additional, Ghayee, Hans K, additional, Bornstein, Stefan R, additional, Dieterich, Peter, additional, Pietzsch, Jens, additional, Wielockx, Ben, additional, Robledo, Mercedes, additional, Qin, Nan, additional, and Eisenhofer, Graeme, additional

Published
2020
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65. Hypoxia pathway proteins regulate the synthesis and release of epinephrine in the mouse adrenal gland

Author

Watts, Deepika, primary, Bechmann, Nicole, additional, Meneses, Ana, additional, Poutakidou, Ioanna K., additional, Kaden, Denise, additional, Conrad, Catleen, additional, Krüger, Anja, additional, Stein, Johanna, additional, El-Armouche, Ali, additional, Chavakis, Triantafyllos, additional, Eisenhofer, Graeme, additional, Peitzsch, Mirko, additional, and Wielockx, Ben, additional

Published
2020
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66. Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity

Author

Kalafati, Lydia, primary, Kourtzelis, Ioannis, additional, Schulte-Schrepping, Jonas, additional, Li, Xiaofei, additional, Hatzioannou, Aikaterini, additional, Grinenko, Tatyana, additional, Hagag, Eman, additional, Sinha, Anupam, additional, Has, Canan, additional, Dietz, Sevina, additional, de Jesus Domingues, Antonio Miguel, additional, Nati, Marina, additional, Sormendi, Sundary, additional, Neuwirth, Ales, additional, Chatzigeorgiou, Antonios, additional, Ziogas, Athanasios, additional, Lesche, Mathias, additional, Dahl, Andreas, additional, Henry, Ian, additional, Subramanian, Pallavi, additional, Wielockx, Ben, additional, Murray, Peter, additional, Mirtschink, Peter, additional, Chung, Kyoung-Jin, additional, Schultze, Joachim L., additional, Netea, Mihai G., additional, Hajishengallis, George, additional, Verginis, Panayotis, additional, Mitroulis, Ioannis, additional, and Chavakis, Triantafyllos, additional

Published
2020
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70. Reprogramming of glucocorticoid receptor function by hypoxia.

Author

Vanderhaeghen, Tineke, Timmermans, Steven, Watts, Deepika, Paakinaho, Ville, Eggermont, Melanie, Vandewalle, Jolien, Wallaeys, Charlotte, Van Wyngene, Lise, Van Looveren, Kelly, Nuyttens, Louise, Dewaele, Sylviane, Vanden Berghe, Joke, Lemeire, Kelly, De Backer, Joey, Dirkx, Laura, Vanden Berghe, Wim, Caljon, Guy, Ghesquière, Bart, De Bosscher, Karolien, and Wielockx, Ben

Abstract

Here, we investigate the impact of hypoxia on the hepatic response of glucocorticoid receptor (GR) to dexamethasone (DEX) in mice via RNA‐sequencing. Hypoxia causes three types of reprogramming of GR: (i) much weaker induction of classical GR‐responsive genes by DEX in hypoxia, (ii) a number of genes is induced by DEX specifically in hypoxia, and (iii) hypoxia induces a group of genes via activation of the hypothalamic–pituitary–adrenal (HPA) axis. Transcriptional profiles are reflected by changed GR DNA‐binding as measured by ChIP sequencing. The HPA axis is induced by hypothalamic HIF1α and HIF2α activation and leads to GR‐dependent lipolysis and ketogenesis. Acute inflammation, induced by lipopolysaccharide, is prevented by DEX in normoxia but not during hypoxia, and this is attributed to HPA axis activation by hypoxia. We unfold new physiological pathways that have consequences for patients suffering from GC resistance. Synopsis: This study investigates the impact of hypoxia on hepatic GR function and unfolds new physiological pathways that might have implications for patients suffering from GC resistance. Hypoxia stabilizes HIF1α and HIF2α at the hypothalamus and activates the HPA axis which leads to increased GR‐dependent lipolysis and ketogenesis.Hypoxia induces transcriptional reprogramming of the GR.In hypoxic conditions, DEX is no longer able to protect against acute inflammation. [ABSTRACT FROM AUTHOR]

Published
2022
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72. Inhibition of matrix metalloproteinases blocks lethal hepatitis and apoptosis induced by tumor necrosis factor and allows safe antitumor therapy

Author

Wielockx, Ben, Lannoy, Katrien, Shapiro, Steven D., Itoh, Takeshi, Itohara, Shigeyoshi, Vandekerckhove, Joel, and Libert, Claude

Abstract

Acute and fulminant liver failure induced by viral hepatitis, alcohol or other hepatotoxic drugs, are associated with tumor necrosis factor (TNF) production. In a mouse model of lethal hepatitis induced by TNF, apoptosis and necrosis of hepatocytes, but also lethality, hypothermia and influx of leukocytes into the liver, are prevented by a broad-spectrum matrix metalloproteinase (MMP) inhibitor, BB-94. Mice deficient in MMP-2, MMP-3 or MMP-9 had lower levels of apoptosis and necrosis of hepatocytes, and better survival. We found induction of MMP-9 activity and fibronectin degradation. Our findings suggest that several MMPs play a critical role in acute, fulminant hepatitis by degrading the extracellular matrix and allowing massive leukocyte influx in the liver. BB-94 also prevented lethality in TNF/interferon-[gamma] therapy in tumor-bearing mice. A broad-spectrum MMP inhibitor may be potentially useful for the treatment of patients with acute and perhaps chronic liver failure, and in cancer therapies using inflammatory cytokines., Author(s): Ben Wielockx [1]; Katrien Lannoy [1]; Steven D. Shapiro [2]; Takeshi Itoh [3]; Shigeyoshi Itohara [4]; Joel Vandekerckhove [5]; Claude Libert (corresponding author) [1] The abrupt or chronic loss [...]

Published
2001
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73. Obesity-associated lipidomic remodeling of the adrenal gland indicates an important role of the FADS2-arachidonic acid axis in adrenocortical hormone production

Author

Witt, Anke, primary, Mirtschink, Peter, additional, Palladini, Alessandra, additional, Mateska, Ivona, additional, Abdelmegeed, Heba, additional, Grzybek, Michal, additional, Wielockx, Ben, additional, Peitzsch, Mirko, additional, Coskun, Ünal, additional, Chavakis, Triantafyllos, additional, and Alexaki, Vasileia Ismini, additional

Published
2020
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74. HIF1α is an essential regulator of steroidogenesis in the adrenal gland

Author

Watts, Deepika, primary, Stein, Johanna, additional, Meneses, Ana, additional, Bechmann, Nicole, additional, Neuwirth, Ales, additional, Kaden, Denise, additional, Krüger, Anja, additional, Sinha, Anupam, additional, Alexaki, Vasileia Ismini, additional, Perez-Rivas, Luis Gustavo, additional, Kircher, Stefan, additional, Martinez, Antoine, additional, Theodoropoulou, Marily, additional, Eisenhofer, Graeme, additional, Peitzsch, Mirko, additional, El-Armouche, Ali, additional, Chavakis, Triantafyllos, additional, and Wielockx, Ben, additional

Published
2020
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75. HIF2α is a Direct Regulator of Neutrophil Motility

Author

Sormendi, Sundary, primary, Deygas, Mathieu, additional, Sinha, Anupam, additional, Krüger, Anja, additional, Kourtzelis, Ioannis, additional, Le Lay, Gregoire, additional, Bernard, Mathilde, additional, Sáez, Pablo J., additional, Gerlach, Michael, additional, Franke, Kristin, additional, Meneses, Ana, additional, Kräter, Martin, additional, Palladini, Alessandra, additional, Guck, Jochen, additional, Coskun, Ünal, additional, Chavakis, Triantafyllos, additional, Vargas, Pablo, additional, and Wielockx, Ben, additional

Published
2020
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77. The ACE-2 in COVID-19: Foe or Friend?

Author

Dalan, Rinkoo, additional, Bornstein, Stefan R., additional, El-Armouche, Ali, additional, Rodionov, Roman N, additional, Markov, Alexander, additional, Wielockx, Ben, additional, Beuschlein, Felix, additional, and Boehm, Bernhard O., additional

Published
2020
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78. Cancer Stem Cells in Pheochromocytoma and Paraganglioma

Author

Scriba, Laura D., primary, Bornstein, Stefan R., additional, Santambrogio, Alice, additional, Mueller, Gregor, additional, Huebner, Angela, additional, Hauer, Julia, additional, Schedl, Andreas, additional, Wielockx, Ben, additional, Eisenhofer, Graeme, additional, Andoniadou, Cynthia L., additional, and Steenblock, Charlotte, additional

Published
2020
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79. Erythropoietin receptor in B cells plays a role in bone remodeling in mice

Author

Deshet-Unger, Naamit, primary, Kolomansky, Albert, additional, Ben-Califa, Nathalie, additional, Hiram-Bab, Sahar, additional, Gilboa, Dafna, additional, Liron, Tamar, additional, Ibrahim, Maria, additional, Awida, Zamzam, additional, Gorodov, Anton, additional, Oster, Howard S., additional, Mittelman, Moshe, additional, Rauner, Martina, additional, Wielockx, Ben, additional, Gabet, Yankel, additional, and Neumann, Drorit, additional

Published
2020
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81. B Cell Specific Knockdown of the Erythropoietin (EPO) Receptor Attenuates EPO-Induced Bone Loss in Mice

Author

Kolomansky, Albert, primary, Deshet-Unger, Naamit, primary, Ben-Califa, Nathalie, primary, Awida, Zamzam, primary, Ibrahim, Maria, primary, Liron, Tamar, primary, Hiram-Bab, Sahar, primary, Oster, Howard S., primary, Mittelman, Moshe, primary, Rauner, Martina, primary, Wielockx, Ben, primary, Gabet, Yankel, primary, and Neumann, Drorit, primary

Published
2019
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82. PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling

Author

Egners, Antje, Rezaei, Maryam, Kuzmanov, Aleksandar, Poitz, David M., Streichert, Doreen, Müller-Reichert, Thomas, Wielockx, Ben, and Breier, Georg

Subjects
prolyl hydroxylase domain protein, PDGF-C, tumor progression, tumor angiogenesis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, PDGFR-α, lcsh:RC254-282, Article
Abstract

Cancer cell proliferation and insufficient blood supply can lead to the development of hypoxic areas in the tumor tissue. The adaptation to the hypoxic environment is mediated by a transcriptional complex called hypoxia-inducible factor (HIF). HIF protein levels are tightly controlled by oxygen-dependent prolyl hydroxylase domain proteins (PHDs). However, the precise roles of these enzymes in tumor progression and their downstream signaling pathways are not fully characterized. Here, we study PHD3 function in murine experimental osteosarcoma. Unexpectedly, PHD3 silencing in LM8 cells affects neither HIF-1&alpha, protein levels, nor the expression of various HIF-1 target genes. Subcutaneous injection of PHD3-silenced tumor cells accelerated tumor progression and was accompanied by dramatic phenotypic changes in the tumor vasculature. Blood vessels in advanced PHD3-silenced tumors were enlarged whereas their density was greatly reduced. Examination of the molecular pathways underlying these alterations revealed that platelet-derived growth factor (PDGF)-C signaling is activated in the vasculature of PHD3-deficient tumors. Silencing of PDGF-C depleted tumor growth, increased vessel density and reduced vessel size. Our data show that PHD3 controls tumor growth and vessel architecture in LM8 osteosarcoma by regulating the PDGF-C pathway, and support the hypothesis that different members of the PHD family exert unique functions in tumors.

Published
2018

88. DEL-1 promotes macrophage efferocytosis and clearance of inflammation

Author

Kourtzelis, Ioannis, primary, Li, Xiaofei, additional, Mitroulis, Ioannis, additional, Grosser, Daniel, additional, Kajikawa, Tetsuhiro, additional, Wang, Baomei, additional, Grzybek, Michal, additional, von Renesse, Janusz, additional, Czogalla, Aleksander, additional, Troullinaki, Maria, additional, Ferreira, Anaisa, additional, Doreth, Christian, additional, Ruppova, Klara, additional, Chen, Lan-Sun, additional, Hosur, Kavita, additional, Lim, Jong-Hyung, additional, Chung, Kyoung-Jin, additional, Grossklaus, Sylvia, additional, Tausche, Anne Kathrin, additional, Joosten, Leo A. B., additional, Moutsopoulos, Niki M., additional, Wielockx, Ben, additional, Castrillo, Antonio, additional, Korostoff, Jonathan M., additional, Coskun, Ünal, additional, Hajishengallis, George, additional, and Chavakis, Triantafyllos, additional

Published
2018
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89. Increased epo levels are associated with bone loss in mice lacking phd2 in epo-producing cells

Author

Rauner, Martina, Franke, Kristin, Murray, Marta, Singh, Rashim Pal, Hiram-Bab, Sahar, Platzbecker, Uwe, Gassmann, Max, Socolovsky, Merav, Neumann, Drorit, Gabet, Yankel, Chavakis, Triantafyllos, Hofbauer, Lorenz C, Wielockx, Ben, University of Zurich, and Wielockx, Ben

Subjects
2712 Endocrinology, Diabetes and Metabolism, 2732 Orthopedics and Sports Medicine, bone loss, 10076 Center for Integrative Human Physiology, osteoclast, osteoblast, 570 Life sciences, biology, PHD2, erythropoietin, 10081 Institute of Veterinary Physiology
Published
2016

90. Hematopoietic hypoxia‐inducible factor 2α deficiency ameliorates pathological retinal neovascularization via modulation of endothelial cell apoptosis

Author

Korovina, Irina, primary, Neuwirth, Ales, additional, Sprott, David, additional, Weber, Silvio, additional, Pasha, Sheik Pran Babu Sardar, additional, Gercken, Bettina, additional, Breier, Georg, additional, El-Armouche, Ali, additional, Deussen, Andreas, additional, Karl, Mike O., additional, Wielockx, Ben, additional, Chavakis, Triantafyllos, additional, and Ameln, Anne Klotzsche-von, additional

Published
2018
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94. Hematopoietic stem cells differentiate into restricted myeloid progenitors before cell division

Author

Grinenko, Tatyana, primary, Eugster, Anne, additional, Thielecke, Lars, additional, Ramazs, Beata, additional, Krueger, Anja, additional, Dietz, Sevina, additional, Glauche, Ingmar, additional, Gerbaulet, Alexander, additional, Bonin, Malte von, additional, Basak, Onur, additional, Clevers, Hans, additional, Chavakis, Triantafyllos, additional, and Wielockx, Ben, additional

Published
2018
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95. Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity

Author

Mitroulis, Ioannis, primary, Ruppova, Klara, additional, Wang, Baomei, additional, Chen, Lan-Sun, additional, Grzybek, Michal, additional, Grinenko, Tatyana, additional, Eugster, Anne, additional, Troullinaki, Maria, additional, Palladini, Alessandra, additional, Kourtzelis, Ioannis, additional, Chatzigeorgiou, Antonios, additional, Schlitzer, Andreas, additional, Beyer, Marc, additional, Joosten, Leo A.B., additional, Isermann, Berend, additional, Lesche, Mathias, additional, Petzold, Andreas, additional, Simons, Kai, additional, Henry, Ian, additional, Dahl, Andreas, additional, Schultze, Joachim L., additional, Wielockx, Ben, additional, Zamboni, Nicola, additional, Mirtschink, Peter, additional, Coskun, Ünal, additional, Hajishengallis, George, additional, Netea, Mihai G., additional, and Chavakis, Triantafyllos, additional

Published
2018
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97. Haematopoietic prolyl hydroxylase-1 deficiency promotes M2 macrophage polarization and is both necessary and sufficient to protect against experimental colitis

Author

Van Welden, Sophie, De Vos, Martine, Wielockx, Ben, Tavernier, Simon J., Dullaers, Melissa, Neyt, Sara, Descamps, Benedicte, Devisscher, Lindsey, Devriese, Sarah, Van den Bossche, Lien, Holvoet, Tom, Baeyens, Ann, Correale, Carmen, D'Alessio, Silvia, Vanhove, Christian, De Vos, Filip, Verhasselt, Bruno, Breier, Georg, Lambrecht, Bart N., Janssens, Sophie, Carmeliet, Peter, Danese, Silvio, Elewaut, Dirk, Laukens, Debby, Hindryckx, Pieter, Van Welden, S, De Vos, M, Wielockx, B, Tavernier, Sj, Dullaers, M, Neyt, S, Descamps, B, Devisscher, L, Devriese, S, Van den Bossche, L, Holvoet, T, Baeyens, A, Correale, C, D'Alessio, S, Vanhove, C, De Vos, F, Verhasselt, B, Breier, G, Lambrecht, Bn, Janssens, S, Carmeliet, P, Danese, S, Elewaut, D, Laukens, D, and Hindryckx, P

Subjects
Lipopolysaccharides, Male, Colon, Macrophages, Interleukin-1beta, NF-kappa B, Procollagen-Proline Dioxygenase, Endothelial Cells, Dendritic Cells, macrophages, Hypoxia-Inducible Factor-Proline Dioxygenases, Mice, Inbred C57BL, Mice, Bone Marrow, prolyl hydroxylase-1, Animals, Humans, Colitis, Ulcerative, Female, dendritic cells, haematopoietic cells, Gene Deletion, ulcerative colitis
Abstract

Prolyl hydroxylase domain-containing proteins (PHDs) regulate the adaptation of cells to hypoxia. Pan-hydroxylase inhibition is protective in experimental colitis, in which PHD1 plays a prominent role. However, it is currently unknown how PHD1 targeting regulates this protection and which cell type(s) are involved. Here, we demonstrated that Phd1 deletion in endothelial and haematopoietic cells (Phd1(f/f)Tie2:cre) protected mice from dextran sulphate sodium (DSS)-induced colitis, with reduced epithelial erosions, immune cell infiltration, and colonic microvascular dysfunction, whereas the response of Phd2(f/+)Tie2:cre and Phd3(f/f)Tie2:cre mice to DSS was similar to that of their littermate controls. Using bone marrow chimeras and cell-specific cre mice, we demonstrated that ablation of Phd1 in haematopoietic cells but not in endothelial cells was both necessary and sufficient to inhibit experimental colitis. This effect relied, at least in part, on skewing of Phd1-deficient bone marrow-derived macrophages towards an anti-inflammatory M2 phenotype. These cells showed an attenuated nuclear factor-B-dependent response to lipopolysaccharide (LPS), which in turn diminished endothelial chemokine expression. In addition, Phd1 deficiency in dendritic cells significantly reduced interleukin-1 beta production in response to LPS. Taken together, our results further support the development of selective PHD1 inhibitors for ulcerative colitis, and identify haematopoietic cells as their primary target. Copyright (C) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Published
2016

98. PHD2: from hypoxia regulation to disease progression

Author

Wielockx, Ben and Meneses,Ana

Subjects
Hypoxia
Abstract

Ana M Meneses, Ben Wielockx Heisenberg Research Group, Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany Abstract: Oxygen represents one of the major molecules required for the development and maintenance of life. An adequate response to hypoxia is therefore required for the functioning of the majority of living organisms and relies on the activation of the hypoxia-inducible factor (HIF) pathway. HIF prolyl hydroxylase domain-2 (PHD2) has long been recognized as the major regulator of this response, controlling a myriad of outcomes that range from cell death to proliferation. However, this enzyme has been associated with more pathways, making the role of this protein remarkably complex under distinct pathologies. While a protective role seems to exist in physiological conditions such as erythropoiesis; the picture is more complex during pathologies such as cancer. Since the regulation of this enzyme and its closest family members is currently considered as a possible therapy for various diseases, understanding the different particular roles of this protein is essential. Keywords: Hypoxia, PHD, HIF, inflammation, cancer

Published
2016

99. Increased EPO Levels Are Associated With Bone Loss in Mice Lacking PHD2 in

Author

Rauner, Martina, Franke, Kristin, Murray, Marta, Singh, Rashim-Pal, Hiram-Bab, Sahar, Platzbecker, Uwe, Gassmann, Max, Socolovsky, Merav, Neumann, Drorit, Gabet, Yankel, Chavakis, Triantafyllos, Hofbauer, Lorenz-C., and Wielockx, Ben

Subjects
OSTEOCLAST, Mice, Knockout, purl.org/pe-repo/ocde/ford#3.02.18 [https], Erythropoietin/biosynthesis/genetics, Osteoblasts/metabolism/pathology, Bone Resorption/genetics/metabolism/pathology, purl.org/pe-repo/ocde/ford#3.03.11 [https], Mice, Bone Density/genetics, Hypoxia-Inducible Factor-Proline Dioxygenases/deficiency, BONE LOSS, PHD2, Animals, Osteoclasts/metabolism/pathology, Hematopoietic Stem Cells/metabolism/pathology, OSTEOBLAST, Bone Marrow/metabolism/pathology, ERYTHROPOIETIN
Abstract

The main oxygen sensor hypoxia inducible factor (HIF) prolyl hydroxylase 2 (PHD2) is a critical regulator of tissue homeostasis during erythropoiesis, hematopoietic stem cell maintenance, and wound healing. Recent studies point toward a role for the PHD2‐erythropoietin (EPO) axis in the modulation of bone remodeling, even though the studies produced conflicting results. Here, we used a number of mouse strains deficient of PHD2 in different cell types to address the role of PHD2 and its downstream targets HIF‐1α and HIF‐2α in bone remodeling. Mice deficient for PHD2 in several cell lineages, including EPO‐producing cells, osteoblasts, and hematopoietic cells (CD68:cre‐PHD2f/f) displayed a severe reduction of bone density at the distal femur as well as the vertebral body due to impaired bone formation but not bone resorption. Importantly, using osteoblast‐specific (Osx:cre‐PHD2f/f) and osteoclast‐specific PHD2 knock‐out mice (Vav:cre‐ PHD2f/f), we show that this effect is independent of the loss of PHD2 in osteoblast and osteoclasts. Using different in vivo and in vitro approaches, we show here that this bone phenotype, including the suppression of bone formation, is directly linked to the stabilization of the α‐subunit of HIF‐2, and possibly to the subsequent moderate induction of serum EPO, which directly influenced the differentiation and mineralization of osteoblast progenitors resulting in lower bone density. Taken together, our data identify the PHD2:HIF‐2α:EPO axis as a so far unknown regulator of osteohematology by controlling bone homeostasis. Further, these data suggest that patients treated with PHD inhibitors or EPO should be monitored with respect to their bone status.

Published
2016

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