127 results on '"Peyssonnaux, Carole"'
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2. Hepcidin deficiency in mice impairs white adipose tissue browning possibly due to a defect in de novo adipogenesis
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Deschemin, Jean-Christophe, Ransy, Céline, Bouillaud, Frédéric, Chung, Soonkyu, Galy, Bruno, Peyssonnaux, Carole, and Vaulont, Sophie
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- 2023
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3. The hepatokine FGL1 regulates hepcidin and iron metabolism during anemia in mice by antagonizing BMP signaling
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Sardo, Ugo, Perrier, Prunelle, Cormier, Kevin, Sotin, Manon, Personnaz, Jean, Medjbeur, Thanina, Desquesnes, Aurore, Cannizzo, Lisa, Ruiz-Martinez, Marc, Thevenin, Julie, Billoré, Benjamin, Jung, Grace, Abboud, Elise, Peyssonnaux, Carole, Nemeth, Elizabeta, Ginzburg, Yelena Z., Ganz, Tomas, and Kautz, Léon
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- 2024
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4. Reduced HDL-cholesterol in long COVID-19: A key metabolic risk factor tied to disease severity
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Al-Zadjali, Jamila, Al-Lawati, Amal, Al Riyami, Nafila, Al Farsi, Koukab, Al Jarradi, Najwa, Boudaka, Ammar, Al Barhoumi, Ali, Al Lawati, Mohsen, Al Khaifi, Amani, Musleh, Asma, Gebrayel, Prisca, Vaulont, Sophie, Peyssonnaux, Carole, Edeas, Marvin, and Saleh, Jumana
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- 2024
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5. Low transferrin levels predict heightened inflammation in patients with COVID-19: New insights
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Claise, Catherine, Saleh, Jumana, Rezek, Marwa, Vaulont, Sophie, Peyssonnaux, Carole, and Edeas, Marvin
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- 2022
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6. Neutrophils from hereditary hemochromatosis patients are protected from iron excess and are primed
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Renassia, Cyril, Louis, Sabine, Cuvellier, Sylvain, Boussetta, Nadia, Deschemin, Jean-Christophe, Borderie, Didier, Bailly, Karine, Poupon, Joel, Dang, Pham My-Chan, El-Benna, Jamel, Manceau, Sandra, Lefrère, François, Vaulont, Sophie, and Peyssonnaux, Carole
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- 2020
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7. Iron: Innocent bystander or vicious culprit in COVID-19 pathogenesis?
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Edeas, Marvin, Saleh, Jumana, and Peyssonnaux, Carole
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- 2020
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8. Epidermal hepcidin is required for neutrophil response to bacterial infection
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Malerba, Mariangela, Louis, Sabine, Cuvellier, Sylvain, Shambat, Srikanth Mairpady, Hua, Camille, Gomart, Camille, Fouet, Agnes, Ortonne, Nicolas, Decousser, Jean-Winoc, Zinkernagel, Annelies S., Mathieu, Jacques R.R., and Peyssonnaux, Carole
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Bacterial infections -- Analysis -- Health aspects ,Diseases -- Canada -- France -- Analysis -- Health aspects ,Antibiotics -- Analysis -- Health aspects ,Proteases -- Analysis -- Health aspects ,Skin -- Analysis -- Health aspects ,Disease transmission ,Disease susceptibility ,Hormones ,Necrotizing fasciitis ,Peptides ,Infection ,Novels ,Health care industry - Abstract
Novel approaches for adjunctive therapy are urgently needed for complicated infections and patients with compromised immunity. Necrotizing fasciitis (NF) is a destructive skin and soft tissue infection. Despite treatment with systemic antibiotics and radical debridement of necrotic tissue, lethality remains high. The key iron regulatory hormone hepcidin was originally identified as a cationic antimicrobial peptide (AMP), but its putative expression and role in the skin, a major site of AMP production, have never been investigated. We report here that hepcidin production is induced in the skin of patients with group A Streptococcus (GAS) NF. In a GAS-induced NF model, mice lacking hepcidin in keratinocytes failed to restrict systemic spread of infection from an initial tissue focus. Unexpectedly, this effect was due to its ability to promote production of the CXCL1 chemokine by keratinocytes, resulting in neutrophil recruitment. Unlike CXCL1, hepcidin is resistant to degradation by major GAS proteases and could therefore serve as a reservoir to maintain steady-state levels of CXCL1 in infected tissue. Finally, injection of synthetic hepcidin at the site of infection can limit or completely prevent systemic spread of GAS infection, suggesting that hepcidin agonists could have a therapeutic role in NF., Introduction Necrotizing fasciitis (NF) is an infection characterized by widespread necrosis of the skin, subcutaneous tissues, and fascia that was first described by Hippocrates in the 5th century (1). The [...]
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- 2020
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9. Erythropoietin downregulates red blood cell clearance, increasing transfusion efficacy in severely anemic recipients.
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Casimir, Madeleine, Colard, Martin, Dussiot, Michael, Roussel, Camille, Martinez, Anaïs, Peyssonnaux, Carole, Mayeux, Patrick, Benghiat, Samantha, Manceau, Sandra, Francois, Anne, Marin, Nathalie, Pène, Frédéric, Buffet, Pierre A., Hermine, Olivier, and Amireault, Pascal
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- 2023
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10. New insights into the links between hypoxia and iron homeostasis
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Renassia, Cyril and Peyssonnaux, Carole
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- 2019
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11. Iron Regulatory Protein 1 Sustains Mitochondrial Iron Loading and Function in Frataxin Deficiency
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Martelli, Alain, Schmucker, Stéphane, Reutenauer, Laurence, Mathieu, Jacques R.R., Peyssonnaux, Carole, Karim, Zoubida, Puy, Hervé, Galy, Bruno, Hentze, Matthias W., and Puccio, Hélène
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- 2015
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12. Preeclamptic Plasma Induces Transcription Modifications Involving the AP-1 Transcriptional Regulator JDP2 in Endothelial Cells
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Calicchio, Rosamaria, Buffat, Christophe, Mathieu, Jacques R., Ben Salem, Nour, Mehats, Celine, Jacques, Sébastien, Hertig, Alexandre, Berkane, Nadia, Grevoul-Fresquet, Julie, Simeoni, Umberto, Peyssonnaux, Carole, Gavard, Julie, Vaiman, Daniel, and Miralles, Francisco
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- 2013
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13. The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions
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Mastrogiannaki, Maria, Matak, Pavle, and Peyssonnaux, Carole
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- 2013
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14. Pharmacologic Augmentation of Hypoxia-Inducible Factor-1α with Mimosine Boosts the Bactericidal Capacity of Phagocytes
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Zinkernagel, Annelies S., Peyssonnaux, Carole, Johnson, Randall S., and Nizet, Victor
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- 2008
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15. Lack of iron-related phenotype in Sp6 intestinal knockout mice
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Matak, Pavle, Deschemin, Jean-Christophe, Peyssonnaux, Carole, and Vaulont, Sophie
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- 2011
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16. Hypoxia interferes with aryl hydrocarbon receptor pathway in hCMEC/D3 human cerebral microvascular endothelial cells
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Jacob, Aude, Potin, Sophie, Saubaméa, Bruno, Crete, Dominique, Scherrmann, Jean-Michel, Curis, Emmanuel, Peyssonnaux, Carole, and Declèves, Xavier
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- 2015
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17. HIF-2[alpha], but not HIF-1[alpha], promotes iron absorption in mice
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Mastrogiannaki, Maria, Matak, Pavle, Keith, Brian, Simon, M. Celeste, Vaulont, Sophie, and Peyssonnaux, Carole
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DNA binding proteins -- Physiological aspects ,DNA binding proteins -- Genetic aspects ,DNA binding proteins -- Research ,Hypoxia (Aquatic ecology) -- Physiological aspects ,Hypoxia (Aquatic ecology) -- Research ,Iron in the body -- Health aspects ,Iron in the body -- Research ,Iron metabolism disorders -- Genetic aspects ,Iron metabolism disorders -- Control ,Iron metabolism disorders -- Research - Abstract
HIF transcription factors (HIF-1 and HIF-2) are central mediators of cellular adaptation to hypoxia. Because the resting partial pressure of oxygen is low in the intestinal lumen, epithelial cells are believed to be mildly hypoxic. Having recently established a link between HIF and the iron-regulatory hormone hepcidin, we hypothesized that HIFs, stabilized in the hypoxic intestinal epithelium, may also play critical roles in regulating intestinal iron absorption. To explore this idea, we first established that the mouse duodenum, the site of iron absorption in the intestine, is hypoxic and generated conditional knockout mice that lacked either Hif1a or Hif2a specifically in the intestinal epithelium. Using these mice, we found that HIF-1[alpha] was not necessary for iron absorption, whereas HIF-2[alpha] played a crucial role in maintaining iron balance in the organism by directly regulating the transcription of the gene encoding divalent metal transporter 1 (DMT1), the principal intestinal iron transporter. Specific deletion of Hif2a led to a decrease in serum and liver iron levels and a marked decrease in liver hepcidin expression, indicating the involvement of an induced systemic response to counteract the iron deficiency. This finding may provide a basis for the development of new strategies, specifically in targeting HIF-2[alpha], to improve iron homeostasis in patients with iron disorders., Introduction Iron is an essential nutrient and is critical for a multitude of biological processes at the cellular level (including catalyzing essential enzymatic reactions and electron transport) and at the [...]
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- 2009
18. Neutrophils from hereditary hemochromatosis patients are protected from iron excess and are primed
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El Benna, Jamel, Renassia, Cyril, Louis, Sabine, Cuvellier, Sylvain, Boussetta, Nadia, Deschemin, Jean-Christophe, Borderie, Didier, Bailly, Karine, Poupon, Joel, Dang, Pham My-Chan, El-Benna, Jamel, Manceau, Sandra, Lefrère, François, Vaulont, Sophie, Peyssonnaux, Carole, Lab Excellence Inflamex (CRI INSERM U1149 - Bichat Medical Faculty), Université Paris Diderot - Paris 7 (UPD7), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), and Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,medicine.medical_specialty ,Iron Overload ,Neutrophils ,Iron ,Regulator ,Oxidative phosphorylation ,[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Red Cells, Iron, and Erythropoiesis ,Hepcidins ,Hepcidin ,Internal medicine ,medicine ,Animals ,Humans ,ComputingMilieux_MISCELLANEOUS ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,Chemistry ,Genetic disorder ,Hematology ,medicine.disease ,3. Good health ,Respiratory burst ,030104 developmental biology ,Endocrinology ,030220 oncology & carcinogenesis ,Hereditary hemochromatosis ,biology.protein ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Hemochromatosis ,Intracellular - Abstract
Iron is required for the oxidative response of neutrophils to allow the production of reactive oxygen species (ROS). However, neutrophil function may be severely altered in conditions of iron overload, as observed in chronically transfused patients. Therefore, a tight regulation of neutrophil iron homeostasis seems to be critical for avoiding iron toxicity. Hepcidin is the key iron regulator in organisms; however, no studies have investigated its role in maintaining neutrophil iron homeostasis or characterized neutrophil function in patients with hereditary hemochromatosis (HH), a common iron overload genetic disorder that results from a defect in hepcidin production. To explore these issues, we studied 2 mouse models of iron overload: an experimentally induced iron overload model (EIO), in which hepcidin is increased, and a genetic HH model of iron overload with a deletion of hepatic hepcidin. We found that iron-dependent increase of hepatic hepcidin results in neutrophil intracellular iron trapping and consecutive defects in oxidative burst activity. In contrast, in both HH mouse models and HH patients, the lack of hepcidin expression protects neutrophils from toxic iron accumulation. Moreover, systemic iron overload correlated with a surprising neutrophil priming and resulted in a more powerful oxidative burst. Indeed, important factors in neutrophil priming and activation, such as tumor necrosis factor α (TNF-α), VCAM-1, and ICAM-1 are increased in the plasma of HH patients and are associated with an increase in HH neutrophil phagocytosis capacity and a decrease in L-selectin surface expression. This is the first study to characterize neutrophil iron homeostasis and associated functions in patients with HH.
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- 2020
19. HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA–forming microsatellite
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Bayele, Henry K., Peyssonnaux, Carole, Giatromanolaki, Alexandra, Arrais-Silva, Wagner W., Mohamed, Hiba S., Collins, Helen, Giorgio, Selma, Koukourakis, Michael, Johnson, Randall S., Blackwell, Jenefer M., Nizet, Victor, and Srai, Surjit Kaila S.
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- 2007
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20. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs)
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Peyssonnaux, Carole, Zinkernagel, Annelies S., Schuepbach, Reto A., Rankin, Erinn, Vaulont, Sophie, Haase, Volker H., Nizet, Victor, and Johnson, Randall S.
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Homeostasis -- Research ,Iron in the body -- Physiological aspects ,Hypoxia -- Research ,DNA binding proteins -- Physiological aspects - Abstract
Iron is essential for many biological processes, including oxygen delivery, and its supply is tightly regulated. Hepcidin, a small peptide synthesized in the liver, is a key regulator of iron [...]
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- 2007
21. Hepcidin is localised in gastric parietal cells, regulates acid secretion and is induced by Helicobacter pylori infection
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Schwarz, Peggy, Kübler, Johanna A M, Strnad, Pavel, Müller, Katrin, Barth, Thomas F E, Gerloff, Andreas, Feick, Peter, Peyssonnaux, Carole, Vaulont, Sophie, Adler, Guido, and Kulaksiz, Hasan
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- 2012
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22. HIF-1α expression regulates the bactericidal capacity of phagocytes
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Peyssonnaux, Carole, Datta, Vivekanand, Cramer, Thorsten, Doedens, Andrew, Theodorakis, Emmanuel A., Gallo, Richard L., Hurtado-Ziola, Nancy, Nizet, Victor, and Johnson, Randall S.
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- 2005
23. Activation of ERK, Controlled by Rac1 and Cdc42 via Akt, Is Required for Anoikis
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RUL, WILFRID, ZUGASTI, OLIVIER, ROUX, PIERRE, PEYSSONNAUX, CAROLE, EYCHENE, ALAIN, FRANKE, THOMAS F., LENORMAND, PHILIPPE, FORT, PHILIPPE, and HIBNER, URSZULA
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- 2002
24. Mitochondria and microbiota dysfunction in COVID-19 pathogenesis.
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Saleh, Jumana, Peyssonnaux, Carole, Singh, Keshav K, and Edeas, Marvin
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COVID-19 , *REACTIVE oxygen species , *EXTRACELLULAR vesicles , *MITOCHONDRIA , *COVID-19 pandemic , *PLANT mitochondria , *MIDDLE East respiratory syndrome - Abstract
• Mitochondria are the hub of cellular oxidative homeostasis. • Mitochondria are the major source of reactive oxygen species (ROS). • Extracellular mitochondria are found in blood, in circulating platelets and vesicles. • COVID-19 pathogenesis is aggravated by the hyper- inflammatory state. • Inflammation activates events leading to microbiota & mitochondrial oxidative damage. • Mitochondrial damage contributes to coagulopathy, ferroptosis & microbial dysbiosis. • Blood & platelet mitochondria dysfunction may accelerate systemic coagulopathy events. • Targeting mitochondria dysfunction may provide useful therapeutic strategies against COVID-19 pathogenesis. The COVID-19 pandemic caused by the coronavirus (SARS-CoV-2) has taken the world by surprise into a major crisis of overwhelming morbidity and mortality. This highly infectious disease is associated with respiratory failure unusual in other coronavirus infections. Mounting evidence link the accelerated progression of the disease in COVID-19 patients to the hyper-inflammatory state termed as the "cytokine storm" involving major systemic perturbations. These include iron dysregulation manifested as hyperferritinemia associated with disease severity. Iron dysregulation induces reactive oxygen species (ROS) production and promotes oxidative stress. The mitochondria are the hub of cellular oxidative homeostasis. In addition, the mitochondria may circulate "cell-free" in non-nucleated platelets, in extracellular vesicles and mitochondrial DNA is found in the extracellular space. The heightened inflammatory/oxidative state may lead to mitochondrial dysfunction leading to platelet damage and apoptosis. The interaction of dysfunctional platelets with coagulation cascades aggravates clotting events and thrombus formation. Furthermore, mitochondrial oxidative stress may contribute to microbiota dysbiosis, altering coagulation pathways and fueling the inflammatory/oxidative response leading to the vicious cycle of events. Here, we discuss various cellular and systemic incidents caused by SARS-CoV-2 that may critically impact intra and extracellular mitochondrial function, and contribute to the progression and severity of the disease. It is crucial to understand how these key modulators impact COVID-19 pathogenesis in the quest to identify novel therapeutic targets that may reduce fatal outcomes of the disease. [ABSTRACT FROM AUTHOR]
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- 2020
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25. Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing.
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Bessman, Nicholas J., Mathieu, Jacques R. R., Renassia, Cyril, Lei Zhou, Fung, Thomas C., Fernandez, Keith C., Austin, Christine, Moeller, Jesper B., Zumerle, Sara, Louis, Sabine, Vaulont, Sophie, Ajami, Nadim J., Sokol, Harry, Putzel, Gregory G., Arvedson, Tara, Sockolow, Robbyn E., Lakhal-Littleton, Samira, Cloonan, Suzanne M., Arora, Manish, and Peyssonnaux, Carole
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- 2020
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26. Erythropoietin Downregulates Red Blood Cell Clearance in Mice
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Colard, Martin, Dussiot, Michaël, Martinez, Anaïs, Peyssonnaux, Carole, Mayeux, Patrick, Benghiat, Fleur Samantha, Buffet, Pierre, Hermine, Olivier, and Amireault, Pascal
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- 2019
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27. Iron Regulator Hepcidin Impairs Macrophage-Dependent Cardiac Repair After Injury.
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Zlatanova, Ivana, Pinto, Cristina, Bonnin, Philippe, Mathieu, Jacques R.R., Bakker, Wineke, Vilar, Jose, Lemitre, Mathilde, Voehringer, David, Vaulont, Sophie, Peyssonnaux, Carole, and Silvestre, Jean-Sébastien
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- 2019
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28. BioIron Abstracts - ANALYSIS OF TISSUE SPECIFIC KNOCKOUTS OF HEPCIDIN
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Zumerle, Sara, Mathieu, Jacques, Delga, Stéphanie, Viatte, Lydie, Vaulont, Sophie, and Peyssonnaux, Carole
- Published
- 2013
29. Basal expression of copper transporter 1 in intestinal epithelial cells is regulated by hypoxia-inducible factor 2α
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Pourvali, Katayoun, Matak, Pavle, Latunde-Dada, Gladys O., Solomou, Solomis, Mastrogiannaki, Maria, Peyssonnaux, Carole, and Sharp, Paul A.
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- 2012
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30. Deletion of HIF-2α in the enterocytes decreases the severity of tissue iron loading in hepcidin knockout mice
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Mastrogiannaki, Maria, Matak, Pavle, Delga, Stéphanie, Deschemin, Jean-Christophe, Vaulont, Sophie, and Peyssonnaux, Carole
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- 2012
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31. Pulmonary Iron Homeostasis in Hepcidin Knockout Mice.
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Deschemin, Jean-Christophe, Mathieu, Jacques R. R., Zumerle, Sara, Peyssonnaux, Carole, and Vaulont, Sophie
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HEPCIDIN ,INFLAMMATION ,IRON ,FERRITIN ,ALVEOLAR macrophages - Abstract
Pulmonary iron excess is deleterious and contributes to a range of chronic and acute inflammatory diseases. Optimal lung iron concentration is maintained through dynamic regulation of iron transport and storage proteins. The iron-regulatory hormone hepcidin is also expressed in the lung. In order to better understand the interactions between iron-associated molecules and the hepcidin-ferroportin axis in lung iron balance, we examined lung physiology and inflammatory responses in two murine models of systemic iron-loading, either hepcidin knock-out (Hepc KO) or liver-specific hepcidin KO mice (Hepc KOliv), which do (Hepc KOliv) or do not (Hepc KO) express lung hepcidin. We have found that increased plasma iron in Hepc KO mice is associated with increased pulmonary iron levels, consistent with increased cellular iron uptake by pulmonary epithelial cells, together with an increase at the apical membrane of the cells of the iron exporter ferroportin, consistent with increased iron export in the alveoli. Subsequently, alveolar macrophages (AM) accumulate iron in a non-toxic form and this is associated with elevated production of ferritin. The accumulation of iron in the lung macrophages of hepcidin KO mice contrasts with splenic and hepatic macrophages which contain low iron levels as we have previously reported. Hepc KOliv mice with liver-specific hepcidin deficiency demonstrated same pulmonary iron overload profile as the Hepc KO mice, suggesting that pulmonary hepcidin is not critical in maintaining local iron homeostasis. In addition, the high iron load in the lung of Hepc KO mice does not appear to enhance acute lung inflammation or injury. Lastly, we have shown that intraperitoneal LPS injection is not associated with pulmonary hepcidin induction, despite high levels of inflammatory cytokines. However, intranasal LPS injection stimulates a hepcidin response, likely derived from AM, and alters pulmonary iron content in Hepc KO mice. [ABSTRACT FROM AUTHOR]
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- 2017
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32. Copper Deficiency Leads to Anemia, Duodenal Hypoxia, Upregulation of HIF-2α and Altered Expression of Iron Absorption Genes in Mice.
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Matak, Pavle, Zumerle, Sara, Mastrogiannaki, Maria, El Balkhi, Souleiman, Delga, Stephanie, Mathieu, Jacques R. R., Canonne-Hergaux, François, Poupon, Joel, Sharp, Paul A., Vaulont, Sophie, and Peyssonnaux, Carole
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COPPER deficiency ,HYPOXIA-inducible factors ,ANEMIA ,GENE expression ,CYTOLOGY ,MOLECULAR biology ,LABORATORY mice - Abstract
Iron and copper are essential trace metals, actively absorbed from the proximal gut in a regulated fashion. Depletion of either metal can lead to anemia. In the gut, copper deficiency can affect iron absorption through modulating the activity of hephaestin - a multi-copper oxidase required for optimal iron export from enterocytes. How systemic copper status regulates iron absorption is unknown. Mice were subjected to a nutritional copper deficiency-induced anemia regime from birth and injected with copper sulphate intraperitoneally to correct the anemia. Copper deficiency resulted in anemia, increased duodenal hypoxia and Hypoxia inducible factor 2α (HIF-2α) levels, a regulator of iron absorption. HIF-2α upregulation in copper deficiency appeared to be independent of duodenal iron or copper levels and correlated with the expression of iron transporters (Ferroportin - Fpn, Divalent Metal transporter – Dmt1) and ferric reductase – Dcytb. Alleviation of copper-dependent anemia with intraperitoneal copper injection resulted in down regulation of HIF-2α-regulated iron absorption genes in the gut. Our work identifies HIF-2α as an important regulator of iron transport machinery in copper deficiency. [ABSTRACT FROM AUTHOR]
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- 2013
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33. HIF1α and pancreatic β-cell development.
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Heinis, Mylène, Soggia, Andrea, Bechetoille, Camille, Simon, Marie-Thérèse, Peyssonnaux, Carole, Rustin, Pierre, Scharfmann, Raphael, and Duvillié, Bertrand
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EMBRYOLOGY ,BLOOD flow measurement ,CELL differentiation ,PHYSIOLOGICAL effects of oxygen ,PANCREATIC analysis - Abstract
During early embryogenesis, the pancreas shows a paucity of blood flow, and oxygen tension, the partial pressure of oxygen (pO
2 ), is low. Later, the blood flow increases as β-cell differentiation occurs. We have previously reported that pO2 controls β-cell development in rats. Here, we checked that hypoxia inducible factor 1α (HIF1α) is essential for this control. First, we demonstrated that the effect of pO2 on β-cell differentiation in vitro was independent of epitheliomesenchymal interactions and that neither oxidative nor energetic stress occurred. Second, the effect of pO2 on pancreas development was shown to be conserved among species, since increasing pO2 to 21 vs. 3% also induced-cell differentiation in mouse (7-fold, P<0.001) and human fetal pancreas. Third, the effect of hypoxia was mediated by HIF1, since the addition of an HIF1 inhibitor at 3% O2 increased the number of NGN3-expressing progenitors as com- pared to nontreated controls (9.2-fold, P<0.001). In contrast, when we stabilized HIF1α by deleting ex vivo the gene encoding pVHL in E13.5 pancreas from Vhl floxed mice, Ngn3 expression and β-cell development decreased in such Vhl-deleted pancreas compared to controls (2.5 fold, P<0.05, and 6.6-fold, P<0.001, respectively). Taken together, these data demonstrate that HIF1α exerts a negative control over-cell differentiation. [ABSTRACT FROM AUTHOR]- Published
- 2012
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34. Critical Role of HIF-1α in Keratinocyte Defense against Bacterial Infection.
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Peyssonnaux, Carole, Boutin, Adam T., Zinkernagel, Annelies S., Datta, Vivekanand, Nizet, Victor, and Johnson, Randall S.
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KERATINOCYTES , *SKIN diseases , *PEPTIDE antibiotics , *BACTERIAL diseases , *DERMATOLOGY - Abstract
Skin, the first barrier against invading microorganisms, is hypoxic, even under baseline conditions. The transcription factor hypoxia-inducible factor-1α (HIF-1α, the principal regulator of cellular adaptation to low oxygen, is strongly expressed in skin epithelium. HIF-1α is now understood to play a key role in the bactericidal capacity of phagocytic cells such as macrophages and neutrophils. In the skin, keratinocytes provide a direct antibacterial activity through production of antimicrobial peptides, including cathelicidin. Here, we generate mice with a keratinocyte-specific deletion of HIF-1α and examine effects on intrinsic skin immunity. Keratinocyte HIF-1α is seen to provide protection against necrotic skin lesions produced by the pathogen group A Streptococcus. RNA interference studies reveal that HIF-1α regulation of keratinocyte cathelicidin production is critical to their antibacterial function.Journal of Investigative Dermatology (2008) 128, 1964–1968; doi:10.1038/jid.2008.27; published online 6 March 2008 [ABSTRACT FROM AUTHOR]
- Published
- 2008
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35. Pharmacologic Augmentation of Hypoxia-Inducible Factor—la with Mimosine Boosts the Bactericidal Capacity of Phagocytes.
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Zinkernagel, Annelies S., Peyssonnaux, Carole, Johnson, Randall S., and Nizet, Victor
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HYPOXEMIA ,MIMOSINE ,PHAGOCYTES ,STAPHYLOCOCCUS aureus ,PATHOGENIC microorganisms ,SKIN infections ,BACTERIAL diseases ,CELL physiology ,THERAPEUTICS - Abstract
Hypoxia-inducible factor (HIF)-1α is activated on exposure to bacterial pathogens and regulates the innate immune functions of phagocytes. We show here that the HIF-1α agonist mimosine can boost the capacity of human phagocytes and whole blood to kill the leading pathogen Staphylococcus aureus in a dose-dependent fashion and reduce the lesion size in a murine model of S. aureus skin infection. This provides the first proof of principle for a novel approach to the treatment of bacterial infection by pharmacologically augmenting the host phagocytic cell function. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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36. Role of the hypoxia inducible factors in iron metabolism.
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Peyssonnaux, Carole, Nizet, Victor, and Johnson, Randall S.
- Published
- 2008
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37. An Unexpected Role for Hypoxic Response.
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Peyssonnaux, Carole and Johnson, Randall S.
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- 2004
38. A Raf-1 Mutant That Dissociates MEK/Extracellular Signal-Regulated Kinase Activation from Malignant Transformation and Differentiation but Not Proliferation.
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Dhillon, Amardeep S., Meikle, Sharon, Peyssonnaux, Carole, Grindlay, Joan, Kaiser, Christian, Steen, Helge, Shaw, Peter E., Mischak, Harald, Eychène, Alain, and Kolch, Walter
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GENETIC mutation ,PROTEIN binding - Abstract
It is widely thought that the biological outcomes of Raf-1 activation are solely attributable to the activation of the MEK/extracellular signal-regulated kinase (ERK) pathway. However, an increasing number of reports suggest that some Raf-1 functions are independent of this pathway. In this report we show that mutation of the amino-terminal 14-3-3 binding site of Raf-1 uncouples its ability to activate the MEK/ERK pathway from the induction of cell transformation and differentiation. In NIH 3T3 fibroblasts and COS-1 cells, mutation of serine 259 resulted in Raf-1 proteins which activated the MEK/ERK pathway as efficiently as v-Raf. However, in contrast to v-Raf, RafS259 mutants failed to transform. They induced morphological alterations and slightly accelerated proliferation in NIH 3T3 fibroblasts but were not tumorigenic in mice and behaved like wild-type Raf-1 in transformation assays measuring loss of contact inhibition or anchorage-independent growth. Curiously, the RafS259 mutants inhibited focus induction by an activated MEK allele, suggesting that they can hyperactivate negative-feedback pathways. In primary cultures of postmitotic chicken neuroretina cells, RafS259A was able to sustain proliferation to a level comparable to that sustained by the membrane-targeted transforming Raf-1 protein, RafCAAX. In contrast, RafS259A was only a poor inducer of neurite formation in PC12 cells in comparison to RafCAAX. Thus, RafS259 mutants genetically separate MEK/ERK activation from the ability of Raf-1 to induce transformation and differentiation. The results further suggest that RafS259 mutants inhibit signaling pathways required to promote these biological processes. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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39. Ras mediates the cAMP-dependent activation of extracellular signal-regulated kinases (ERKs) in melanocytes.
- Author
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Buscà, Roser, Abbe, Patricia, Mantoux, Fréderic, Aberdam, Edith, Peyssonnaux, Carole, Eychène, Alain, Ortonne, Jean-Paul, and Balloti, Robert
- Subjects
RESEARCH ,SCIENTIFIC method ,MELANOCYTES ,EPITHELIAL cells ,TOXINS ,ANTITOXINS - Abstract
In melanocytes and melanoma cells, cAMP activates extracellular signal-regulated kinases (ERKs) and MEK-1 by an unknown mechanism. We demonstrate that B-Raf is activated by cAMP in melanocytes. A dominant-negative mutant of B-Raf, but not of Raf-1, blocked the cAMP-induced activation of ERK, indicating that B-Raf is the MEK-1 upstream regulator mediating this cAMP effect. Studies using Clostridium sordelii lethal toxin and Clostridium difficile toxin B have suggested that Rap-1 or Ras might transduce cAMP action. We show that Ras, but not Rap-l, is activated cell-specifically and mediates the cAMP-dependent activation of ERKs, while Rap-1 is not involved in this process in melanocytes. Our results suggest a novel, cell-specific mechanism involving Ras small GTPase and B-Raf kinase as mediators of ERK activation by cAMP. Also, in melanocytes, Ras or ERK activation by cAMP is not mediated through protein kinase A activation. Neither the Ras exchange factor, Son of sevenless (SOS), nor the cAMP-responsive Rap-1 exchange factor, Epac, participate in the cAMP-dependent activation of Ras. These findings suggest the existence of a melanocyte-specific Ras exchange factor directly regulated by cAMP. [ABSTRACT FROM AUTHOR]
- Published
- 2000
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40. Differential Regulation of B-Raf Isoforms by Phosphorylation and Autoinhibitory Mechanisms.
- Author
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Hmitou, Isabelle, Druillennec, Sabine, Valluet, Agathe, Peyssonnaux, Carole, and Eychène, Alain
- Subjects
PROTO-oncogenes ,GENETIC engineering ,EXONS (Genetics) ,PHOSPHORYLATION ,GENETIC mutation - Abstract
The B-Raf proto-oncogene encodes several isoforms resulting from alternative splicing in the hinge region upstream of the kinase domain. The presence of exon 8b in the B2-Raf
8b isoform and exon 9b in the B3-Raf9b isoform differentially regulates B-Raf by decreasing and increasing MEK activating and oncogenic activities, respectively. Using different cell systems, we investigated here the molecular basis of this regulation. We show that exons 8b and 9b interfere with the ability of the B-Raf N-terminal region to interact with and inhibit the C-terminal kinase domain, thus modulating the autoinhibition mechanism in an opposite manner. Exons 8b and 9b are flanked by two residues reported to down-regulate B-Raf activity upon phosphorylation. The S365A mutation increased the activity of all B-Raf isoforms, but the effect on B2-Raf8b was more pronounced. This was correlated to the high level of S365 phosphorylation in this isoform, whereas the B3-Raf9b isoform was poorly phosphorylated on this residue. In contrast, S429 was equally phosphorylated in all B-Raf isoforms, but the S429A mutation activated B2-Raf8b , whereas it inhibited B3-Raf9b . These results indicate that phosphorylation on both S365 and S429 participate in the differential regulation of B-Raf isoforms through distinct mechanisms. Finally, we show that autoinhibition and phosphorylation represent independent but convergent mechanisms accounting for B-Raf regulation by alternative splicing. [ABSTRACT FROM AUTHOR]- Published
- 2007
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41. Myeloid HIFs Are Dispensable for Resolution of Inflammation during Skeletal Muscle Regeneration Inflammation during Skeletal Muscle Regeneration.
- Author
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Gondin, Julien, Théret, Marine, Duhamel, Guillaume, Pegan, Katarina, Mathieu, Jacques R. R., Peyssonnaux, Carole, Cuvellier, Sylvain, Latroche, Claire, Chazaud, Bénédicte, Bendahan, David, and Mounier, Rémi
- Subjects
- *
HYPOXIA-inducible factor 1 , *ANTI-inflammatory agents , *MACROPHAGES , *MUSCLE regeneration , *HYPOXEMIA - Abstract
Besides their role in cellular responses to hypoxia, hypoxia-inducible factors (HIFs) are involved in innate immunity and also have anti-inflammatory (M2) functions, such as resolution of inflammation preceding healing. Whereas the first steps of the inflammatory response are associated with proinflammatory (M1) macrophages (MPs), resolution of inflammation is associated with anti-inflammatory MPs exhibiting an M2 phenotype. This M1 to M2 sequence is observed during postinjury muscle regeneration, which provides an excellent paradigm to study the resolution of sterile inflammation. In this study, using in vitro and in vivo approaches in murine models, we demonstrated that deletion of hif1a or hif2a in MPs has no impact on the acquisition of an M2 phenotype. Furthermore, using a multiscale methodological approach, we showed that muscles did not require macrophagic hif1a or hif2a to regenerate. These results indicate that macrophagic HIFs do not play a crucial role during skeletal muscle regeneration induced by sterile tissue damage. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
42. Myeloid HIF-1 Is Protective in Helicobacter pylori-Mediated Gastritis Gastritis.
- Author
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Matak, Pavle, Heinis, Mylène, Mathieu, Jacques R. R., Corriden, Ross, Cuvellier, Sylvain, Delga, Stéphanie, Mounier, Rémi, Rouquette, Alexandre, Raymond, Josette, Lamarque, Dominique, Emile, Jean-François, Nizet, Victor, Touati, Eliette, and Peyssonnaux, Carole
- Subjects
- *
HYPOXIA-inducible factors , *HELICOBACTER pylori , *GASTRITIS , *DISEASE progression , *MACROPHAGES , *THERAPEUTICS - Abstract
Helicobacter pylori infection triggers chronic inflammation of the gastric mucosa that may progress to gastric cancer. The hypoxia-inducible factors (HIFs) are the central mediators of cellular adaptation to low oxygen levels (hypoxia), but they have emerged recently as major transcriptional regulators of immunity and inflammation. No studies have investigated whether H. pylori affects HIF signaling in immune cells and a potential role for HIF in H. pylori-mediated gastritis. HIF-1 and HIF-2 expression was examined in human H. pylori-positive gastritis biopsies. Subsequent experiments were performed in naive and polarized bone marrow-derived macrophages from wild-type (WT) and myeloid HIF-1a-null mice (HIF-1Δmyel). WT and HIF-1Δmyel mice were inoculated with H. pylori by oral gavage and sacrificed 6 mo postinfection. HIF-1 was specifically expressed in macrophages of human H. pylori-positive gastritis biopsies. Macrophage HIF-1 strongly contributed to the induction of proinflammatory genes (IL-6, IL-1β) and inducible NO synthase in response to H. pylori. HIF-2 expression and markers of M2 macrophage differentiation were decreased in response to H. pylori. HIF-1Δmyel mice inoculated with H. pylori for 6 mo presented with a similar bacterial colonization than WT mice but, surprisingly, a global increase of inflammation, leading to a worsening of the gastritis, measured by an increased epithelial cell proliferation. In conclusion, myeloid HIF-1 is protective in H. pylori-mediated gastritis, pointing to the complex counterbalancing roles of innate immune and inflammatory phenotypes in driving this pathology. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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- View/download PDF
43. Targeted disruption of hepcidin in the liver recapitulates the hemochromatotic phenotype.
- Author
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Zumerle, Sara, Mathieu, Jacques R. R,, Delga, Stéphanie, Heinis, Mylène, Viatte, Lydie, Vaulont, Sophie, and Peyssonnaux, Carole
- Subjects
- *
HEPCIDIN , *MACROPHAGES , *HEMOCHROMATOSIS , *HOMEOSTASIS , *IRON in the body , *TISSUES - Abstract
Hepcidin is a 25-amino-acid peptide demonstrated to be the iron regulatory hormone capable of blocking iron absorption from the duodenum and iron release from macrophages. Mutations affecting hepcidin regulators or the hepoidin gene itself cause hemochromatosis, a common genetic disorder. Hepcidin is produced mainly by the liver, but many cells and tissues express iow levels of the hormone. To determine the contribution of these hepcidin-producing tissues in body iron homeostasis, we have developed a new mouse model in which the hepcidin gene can be conditionaiiy inactivated. Here we compare a liver-specific knockout (KO) mouse model with total KO mice. We show that the liver-specific KO mice fully recapitulate the severe iron overload phenotype observed in the total KO mice, with increased plasma iron and massive parenchymal iron accumulation. This result demonstrates that the hepatocyte constitutes the predominant reservoir for systemic hepcidin and that the other tissues are unable to compensate. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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44. Epidermal hepcidin is required for neutrophil response to bacterial infection
- Author
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Mariangela Malerba, Jean-Winoc Decousser, Sabine Louis, Annelies S. Zinkernagel, Nicolas Ortonne, Carole Peyssonnaux, Srikanth Mairpady Shambat, Camille Hua, Camille Gomart, Agnès Fouet, Sylvain Cuvellier, Jacques Mathieu, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Service de dermatologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de pathologie [Mondor], Department of Virology, Bacteriology-Infection Control, Parasitology-Mycology, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), University of Zurich, Peyssonnaux, Carole, and Université de Paris, Institut Cochin, Institut National de la Santé et de la Recherche Médicale INSERM U1016, Centre National de la Recherche Scientifique CNRS UMR8104, F-75014 Paris.
- Subjects
0301 basic medicine ,Keratinocytes ,Proteases ,Chemokine ,Neutrophils ,Streptococcus pyogenes ,Chemokine CXCL1 ,[SDV]Life Sciences [q-bio] ,610 Medicine & health ,2700 General Medicine ,medicine.disease_cause ,Mouse models ,Group A ,[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity ,10234 Clinic for Infectious Diseases ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Hepcidins ,Immunity ,Hepcidin ,Bacterial infections ,Streptococcal Infections ,Medicine ,Animals ,Humans ,Fasciitis, Necrotizing ,ComputingMilieux_MISCELLANEOUS ,Mice, Knockout ,Infectious disease ,biology ,business.industry ,Streptococcus ,Concise Communication ,General Medicine ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,3. Good health ,CXCL1 ,Disease Models, Animal ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Epidermis ,Chemokines ,business ,Hormone - Abstract
Novel approaches for adjunctive therapy are urgently needed for complicated infections and patients with compromised immunity. Necrotizing fasciitis (NF) is a destructive skin and soft tissue infection. Despite treatment with systemic antibiotics and radical debridement of necrotic tissue, lethality remains high. The key iron regulatory hormone hepcidin was originally identified as a cationic antimicrobial peptide (AMP), but its putative expression and role in the skin, a major site of AMP production, have never been investigated. We report here that hepcidin production is induced in the skin of patients with group A Streptococcus (GAS) NF. In a GAS-induced NF model, mice lacking hepcidin in keratinocytes failed to restrict systemic spread of infection from an initial tissue focus. Unexpectedly, this effect was due to its ability to promote production of the CXCL1 chemokine by keratinocytes, resulting in neutrophil recruitment. Unlike CXCL1, hepcidin is resistant to degradation by major GAS proteases and could therefore serve as a reservoir to maintain steady-state levels of CXCL1 in infected tissue. Finally, injection of synthetic hepcidin at the site of infection can limit or completely prevent systemic spread of GAS infection, suggesting that hepcidin agonists could have a therapeutic role in NF.
- Published
- 2019
45. Iron Boosts Antitumor Type 1 T-cell Responses and Anti-PD1 Immunotherapy.
- Author
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Porte S, Audemard-Verger A, Wu C, Durand A, Level T, Giraud L, Lombès A, Germain M, Pierre R, Saintpierre B, Lambert M, Auffray C, Peyssonnaux C, Goldwasser F, Vaulont S, Alves-Guerra MC, Dentin R, Lucas B, and Martin B
- Subjects
- Animals, Mice, Humans, Cell Line, Tumor, Mice, Inbred C57BL, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Interferon-gamma metabolism, Female, Th1 Cells immunology, Neoplasms immunology, Neoplasms therapy, Neoplasms drug therapy, Iron metabolism, Immunotherapy methods, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
Cancers only develop if they escape immunosurveillance, and the success of cancer immunotherapies relies in most cases on their ability to restore effector T-cell functions, particularly IFNγ production. Revolutionizing the treatment of many cancers, immunotherapies targeting immune checkpoints such as PD1 can increase survival and cure patients. Unfortunately, although immunotherapy has greatly improved the prognosis of patients, not all respond to anti-PD1 immunotherapy, making it crucial to identify alternative treatments that could be combined with current immunotherapies to improve their effectiveness. Here, we show that iron supplementation significantly boosts T-cell responses in vivo and in vitro. The boost was associated with a metabolic reprogramming of T cells in favor of lipid oxidation. We also found that the "adjuvant" effect of iron led to a marked slowdown of tumor cell growth after tumor cell line transplantation in mice. Specifically, our results suggest that iron supplementation promotes antitumor responses by increasing IFNγ production by T cells. In addition, iron supplementation improved the efficacy of anti-PD1 cancer immunotherapy in mice. Finally, our study suggests that, in patients with cancer, the quality and efficacy of the antitumor response following anti-PD1 immunotherapy may be modulated by plasma ferritin levels. In summary, our results suggest the benefits of iron supplementation on the reactivation of antitumor responses and support the relevance of a fruitful association between immunotherapy and iron supplementation., (©2024 American Association for Cancer Research.)
- Published
- 2024
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- View/download PDF
46. CARD9 in neutrophils protects from colitis and controls mitochondrial metabolism and cell survival.
- Author
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Danne C, Michaudel C, Skerniskyte J, Planchais J, Magniez A, Agus A, Michel ML, Lamas B, Da Costa G, Spatz M, Oeuvray C, Galbert C, Poirier M, Wang Y, Lapière A, Rolhion N, Ledent T, Pionneau C, Chardonnet S, Bellvert F, Cahoreau E, Rocher A, Arguello RR, Peyssonnaux C, Louis S, Richard ML, Langella P, El-Benna J, Marteyn B, and Sokol H
- Subjects
- Mice, Animals, Neutrophils metabolism, Cell Survival, Inflammation metabolism, Mice, Knockout, Mitochondria metabolism, Dextran Sulfate toxicity, Disease Models, Animal, Mice, Inbred C57BL, CARD Signaling Adaptor Proteins metabolism, Colitis chemically induced, Colitis prevention & control, Inflammatory Bowel Diseases
- Abstract
Objectives: Inflammatory bowel disease (IBD) results from a combination of genetic predisposition, dysbiosis of the gut microbiota and environmental factors, leading to alterations in the gastrointestinal immune response and chronic inflammation. Caspase recruitment domain 9 ( Card9 ), one of the IBD susceptibility genes, has been shown to protect against intestinal inflammation and fungal infection. However, the cell types and mechanisms involved in the CARD9 protective role against inflammation remain unknown., Design: We used dextran sulfate sodium (DSS)-induced and adoptive transfer colitis models in total and conditional CARD9 knock-out mice to uncover which cell types play a role in the CARD9 protective phenotype. The impact of Card9 deletion on neutrophil function was assessed by an in vivo model of fungal infection and various functional assays, including endpoint dilution assay, apoptosis assay by flow cytometry, proteomics and real-time bioenergetic profile analysis (Seahorse)., Results: Lymphocytes are not intrinsically involved in the CARD9 protective role against colitis. CARD9 expression in neutrophils, but not in epithelial or CD11c+cells, protects against DSS-induced colitis. In the absence of CARD9, mitochondrial dysfunction increases mitochondrial reactive oxygen species production leading to the premature death of neutrophilsthrough apoptosis, especially in oxidative environment. The decreased functional neutrophils in tissues might explain the impaired containment of fungi and increased susceptibility to intestinal inflammation., Conclusion: These results provide new insight into the role of CARD9 in neutrophil mitochondrial function and its involvement in intestinal inflammation, paving the way for new therapeutic strategies targeting neutrophils., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2023
- Full Text
- View/download PDF
47. The hepatokine FGL1 regulates hepcidin and iron metabolism during the recovery from hemorrhage-induced anemia in mice.
- Author
-
Sardo U, Perrier P, Cormier K, Sotin M, Desquesnes A, Cannizzo L, Ruiz-Martinez M, Thevenin J, Billoré B, Jung G, Abboud E, Peyssonnaux C, Nemeth E, Ginzburg YZ, Ganz T, and Kautz L
- Abstract
As a functional component of erythrocyte hemoglobin, iron is essential for oxygen delivery to all tissues in the body. The liver-derived peptide hepcidin is the master regulator of iron homeostasis. During anemia, the erythroid hormone erythroferrone regulates hepcidin synthesis to ensure adequate supply of iron to the bone marrow for red blood cells production. However, mounting evidence suggested that another factor may exert a similar function. We identified the hepatokine FGL1 as a previously undescribed suppressor of hepcidin that is induced in the liver in response to hypoxia during the recovery from anemia and in thalassemic mice. We demonstrated that FGL1 is a potent suppressor of hepcidin in vitro and in vivo . Deletion of Fgl1 in mice results in a blunted repression of hepcidin after bleeding. FGL1 exerts its activity by direct binding to BMP6, thereby inhibiting the canonical BMP-SMAD signaling cascade that controls hepcidin transcription., Key Points: 1/ FGL1 regulates iron metabolism during the recovery from anemia. 2/ FGL1 is an antagonist of the BMP/SMAD signaling pathway.
- Published
- 2023
- Full Text
- View/download PDF
48. Host and microbiota derived extracellular vesicles: Crucial players in iron homeostasis.
- Author
-
Daou Y, Falabrègue M, Pourzand C, Peyssonnaux C, and Edeas M
- Abstract
Iron is a double-edged sword. It is vital for all that's living, yet its deficiency or overload can be fatal. In humans, iron homeostasis is tightly regulated at both cellular and systemic levels. Extracellular vesicles (EVs), now known as major players in cellular communication, potentially play an important role in regulating iron metabolism. The gut microbiota was also recently reported to impact the iron metabolism process and indirectly participate in regulating iron homeostasis, yet there is no proof of whether or not microbiota-derived EVs interfere in this relationship. In this review, we discuss the implication of EVs on iron metabolism and homeostasis. We elaborate on the blooming role of gut microbiota in iron homeostasis while focusing on the possible EVs contribution. We conclude that EVs are extensively involved in the complex iron metabolism process; they carry ferritin and express transferrin receptors. Bone marrow-derived EVs even induce hepcidin expression in β-thalassemia. The gut microbiota, in turn, affects iron homeostasis on the level of iron absorption and possibly macrophage iron recycling, with still no proof of the interference of EVs. This review is the first step toward understanding the multiplex iron metabolism process. Targeting extracellular vesicles and gut microbiota-derived extracellular vesicles will be a huge challenge to treat many diseases related to iron metabolism alteration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Daou, Falabrègue, Pourzand, Peyssonnaux and Edeas.)
- Published
- 2022
- Full Text
- View/download PDF
49. The transcription factor HIF-1α mediates plasticity of NKp46+ innate lymphoid cells in the gut.
- Author
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Krzywinska E, Sobecki M, Nagarajan S, Zacharjasz J, Tambuwala MM, Pelletier A, Cummins E, Gotthardt D, Fandrey J, Kerdiles YM, Peyssonnaux C, Taylor CT, Sexl V, and Stockmann C
- Subjects
- Animals, Biomarkers, Disease Susceptibility, Gene Expression, Gene Expression Profiling, Homeostasis, Immunity, Mucosal, Immunophenotyping, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Lymphocyte Subsets, Mice, Mice, Knockout, Microbiota, Single-Cell Analysis, Antigens, Ly metabolism, Cell Plasticity immunology, Gastrointestinal Tract physiology, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Immunity, Innate, Intraepithelial Lymphocytes immunology, Intraepithelial Lymphocytes metabolism, Natural Cytotoxicity Triggering Receptor 1 metabolism
- Abstract
Gut innate lymphoid cells (ILCs) show remarkable phenotypic diversity, yet microenvironmental factors that drive this plasticity are incompletely understood. The balance between NKp46+, IL-22-producing, group 3 ILCs (ILC3s) and interferon (IFN)-γ-producing group 1 ILCs (ILC1s) contributes to gut homeostasis. The gut mucosa is characterized by physiological hypoxia, and adaptation to low oxygen is mediated by hypoxia-inducible transcription factors (HIFs). However, the impact of HIFs on ILC phenotype and gut homeostasis is not well understood. Mice lacking the HIF-1α isoform in NKp46+ ILCs show a decrease in IFN-γ-expressing, T-bet+, NKp46+ ILC1s and a concomitant increase in IL-22-expressing, RORγt+, NKp46+ ILC3s in the gut mucosa. Single-cell RNA sequencing revealed HIF-1α as a driver of ILC phenotypes, where HIF-1α promotes the ILC1 phenotype by direct up-regulation of T-bet. Loss of HIF-1α in NKp46+ cells prevents ILC3-to-ILC1 conversion, increases the expression of IL-22-inducible genes, and confers protection against intestinal damage. Taken together, our results suggest that HIF-1α shapes the ILC phenotype in the gut., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2022 Krzywinska et al.)
- Published
- 2022
- Full Text
- View/download PDF
50. Serum Iron Protects from Renal Postischemic Injury.
- Author
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Vaugier C, Amano MT, Chemouny JM, Dussiot M, Berrou C, Matignon M, Ben Mkaddem S, Wang PHM, Fricot A, Maciel TT, Grapton D, Mathieu JRR, Beaumont C, Peraldi MN, Peyssonnaux C, Mesnard L, Daugas E, Vrtovsnik F, Monteiro RC, Hermine O, Ginzburg YZ, Benhamou M, Camara NOS, Flamant M, and Moura IC
- Subjects
- Adult, Allografts, Animals, Antioxidants metabolism, Female, Ferritins blood, Glomerular Filtration Rate, Humans, Inflammation, Iron chemistry, Kidney metabolism, Kidney Transplantation, Macrophages cytology, Macrophages metabolism, Male, Mice, Mice, Inbred C57BL, Middle Aged, Monocytes cytology, NF-E2-Related Factor 2 metabolism, Peritonitis metabolism, Prognosis, Reactive Oxygen Species metabolism, Reperfusion Injury metabolism, Signal Transduction, Iron blood, Kidney pathology, Reperfusion Injury prevention & control
- Abstract
Renal transplants remain a medical challenge, because the parameters governing allograft outcome are incompletely identified. Here, we investigated the role of serum iron in the sterile inflammation that follows kidney ischemia-reperfusion injury. In a retrospective cohort study of renal allograft recipients ( n =169), increased baseline levels of serum ferritin reliably predicted a positive outcome for allografts, particularly in elderly patients. In mice, systemic iron overload protected against renal ischemia-reperfusion injury-associated sterile inflammation. Furthermore, chronic iron injection in mice prevented macrophage recruitment after inflammatory stimuli. Macrophages cultured in high-iron conditions had reduced responses to Toll-like receptor-2, -3, and -4 agonists, which associated with decreased reactive oxygen species production, increased nuclear localization of the NRF2 transcription factor, increased expression of the NRF2-related antioxidant response genes, and limited NF- κ B and proinflammatory signaling. In macrophage-depleted animals, the infusion of macrophages cultured in high-iron conditions did not reconstitute AKI after ischemia-reperfusion, whereas macrophages cultured in physiologic iron conditions did. These findings identify serum iron as a critical protective factor in renal allograft outcome. Increasing serum iron levels in patients may thus improve prognosis of renal transplants., (Copyright © 2017 by the American Society of Nephrology.)
- Published
- 2017
- Full Text
- View/download PDF
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