team 4 : Iron metabolism: from regulation to therapy |
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TEAM 4 IRON METABOLISM: FROM REGULATION TO THERAPY
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RESEARCH PROJECTS
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Iron, an essential nutrient, is required for many biological processes but is also toxic in excess. The lack of a mechanism to excrete excess iron makes it crucial for the body to regulate the amount of iron absorbed from the diet by duodenal enterocytes. This regulation is mediated by the hepatic hormone hepcidin. Hepcidin also controls iron release from macrophages that recycle iron and from hepatocytes that store iron. Hepcidin binds to the only known iron export protein, ferroportin, inducing its internalization and degradation and thus limiting the amount of iron released into the plasma. Hepcidin transcription in the liver is controlled by a complex interplay of signals. Most notably, it is increased by plasma and liver iron as a feedback mechanism to maintain stable body iron levels, increased by inflammation as a host defense mechanism to limit extracellular iron availability to microbes, and decreased by erythroid activity to ensure iron supply for erythropoiesis. Dysregulation of hepcidin production contributes to the pathogenesis of many iron disorders: hepcidin deficiency causes iron overload in hereditary hemochromatosis and non-transfused β-thalassemia, whereas overproduction of hepcidin is associated with iron-restricted anemias seen in patients with chronic inflammatory diseases and inherited iron-refractory iron-deficiency anemia (IRIDA), and with liver iron deposits that may contribute to the progression of non-alcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH). |
The best defined regulatory pathway of hepcidin is the BMP/SMAD pathway that mediates the effect of iron on hepcidin and also contributes to the maximal induction of hepcidin by inflammation. Our team has made a major contribution to the field by showing the key role of the ligand BMP6 in this pathway. However, a number of unresolved questions about the regulation of hepcidin by other stimuli remain and our team is currently addressing the following issues: |
- What are the exact molecular mechanisms leading to hepcidin upregulation by inflammation and host defense against extracellular microbes?
- Is iron sequestration in macrophages when hepcidin is high beneficial or toxic for intracellular pathogens such as Salmonella typhimurium?
- By which mechanisms does the liver serine protease matriptase-2 repress hepcidin in vivo? What are matriptase-2 targets and endogeneous inhibitor? What is the efficacy of newly identified small molecule inhibitors of matriptase-2 for treating non-transfused β-thalassemia?
- What are the mechanisms leading to hepcidin dysregulation in NAFLD? What is the relative contribution of hepatocyte versus Kupffer cell iron to the progression of NAFLD to NASH? Can newly designed hepcidin inhibitors prevent iron accumulation in NAFLD and impact progression to NASH?
MEMBERS OF THE TEAM
Former members
ANIMAL AND CELLULAR MODELS / METHODS
- Mouse models for disorders of iron metabolism (Hfe KO, Hjv KO, Tfr2 KO, Tmprss6 KO, Alk3 KO)
- Mouse models for studying the mechanisms of anemia of inflammation (Inhbb KO, Il6 KO, Stat3 KO)
- Bone Marrow Derived Macrophages
- Primary mouse hepatocyte isolation and culture
- Expertise in molecular biology (including cloning, quantitative PCR, chromatin immunoprecipitation), biochemistry (Western blotting), and histology (including Perl’s staining, immunohistochemistry, immunohistofluorescence, confocal imaging, in situ hybridization)
- Production and purification of polyclonal antibodies against iron transporters
- Expertise in epidemiological genetics of complex traits in humans (M. Martinez)
Publications (selection)
ALK3 undergoes ligand-independent homodimerization and BMP-induced heterodimerization with ALK2.
Traeger L, Gallitz I, Sekhri R, Bäumer N, Kuhlmann T, Kemming C, Holtkamp M, Müller JC, Karst U, Canonne-Hergaux F, Muckenthaler MU, Bloch DB, Olschewski A, Bartnikas TB, Steinbicker AU.
Free Radic Biol Med 2018, 129:127-137.
The histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity.
Bricambert J, Alves-Guerra MC, Esteves P, Prip-Buus C, Bertrand-Michel J, Guillou H, Chang CJ, Vander Wal MN, Canonne-Hergaux F, Mathurin P, Raverdy V, Pattou F, Girard J, Postic C, Dentin R.
Nat Commun 2018, 29:2092.
Deletion of BMP6 worsens the phenotype of HJV-deficient mice and attenuates hepcidin levels reached after LPS challenge.
Latour C, Besson-Fournier C, Gourbeyre O, Meynard D, Roth MP, Coppin H.
Blood 2017, 130:2339-2343.
Hepcidin upregulation by inflammation is independent of Smad1/5/8 signaling by activin B.
Besson-Fournier C, Gineste A, Latour C, Gourbeyre O, Meynard D, Martin P, Oswald E, Coppin H, Roth MP.
Blood 2017, 129:533-536.
Erythroferrone contributes to hepcidin repression in a mouse model of malarial anemia.
Latour C, Wlodarczyk MF, Jung G, Gineste A, Blanchard N, Ganz T, Roth MP, Coppin H, Kautz L.
Haematologica 2017, 102:60-68.
Iron- and Hepcidin-Independent Downregulation of the Iron Exporter Ferroportin in Macrophages during Salmonella Infection.
Willemetz A, Beatty S, Richer E, Rubio A, Auriac A, Milkereit RJ, Thibaudeau O, Vaulont S, Malo D, Canonne-Hergaux F.
Front Immunol 2017, 8:498.
Acute loss of the hepatic endo-lysosomal system in vivo causes compensatory changes in iron homeostasis.
Metzendorf C, Zeigerer A, Seifert S, Sparla R, Najafi B, Canonne-Hergaux F, Zerial M, Muckenthaler MU.
Sci Rep 2017, 7:4023.
Activin inhibition limits early innate immune response in rat kidney allografts-a pilot study.
Palin NK, Savikko J, Pasternack A, Rintala JM, Kalra B, Mistry S, Kumar A, Roth MP, Helin H, Ritvos O.
Transpl Int 2017, 30:96-107.
Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice.
Nai A, Rubio A, Campanella A, Gourbeyre O, Artuso I, Bordini J, Gineste A, Latour C, Besson-Fournier C, Lin HY, Coppin H, Roth MP, Camaschella C, Silvestri L, Meynard D.
Blood 2016, 127:2327-36.
Differing impact of the deletion of hemochromatosis-associated molecules HFE and transferrin receptor-2 on the iron phenotype of mice lacking bone morphogenetic protein 6 or hemojuvelin.
Latour C, Besson-Fournier C, Meynard D, Silvestri L, Gourbeyre O, Aguilar-Martinez P, Schmidt PJ, Fleming MD, Roth MP, Coppin H.
Hepatology 2016, 63:126-37.
Further support for the association of GNPAT variant rs11558492 with severe iron overload in hemochromatosis.
Besson-Fournier C, Martinez M, Vinel JP, Aguilar-Martinez P, Coppin H, Roth MP.
Hepatology 2016, 63:2054-5.
Evidence for IL-6/STAT3-independent induction of lipocalin-2 in the liver of mice infected with Escherichia coli.
Gineste A, Martin P, Oswald E, Coppin H, Roth MP.
Hepatology 2016, 63:673-4.
Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance.
Popineau L, Morzyglod L, Carré N, Caüzac M, Bossard P, Prip-Buus C, Lenoir V, Ragazzon B, Fauveau V, Robert L, Guilmeau S, Postic C, Komatsu M, Canonne-Hergaux F, Guillou H, Burnol AF.
Mol Cell Biol 2016, 36:2168-81.
Iron gene expression profile in atherogenic Mox macrophages.
Marques L, Negre-Salvayre A, Costa L, Canonne-Hergaux F.
Biochim Biophys Acta 2016, 1862:1137-46.
The microbiota shifts the iron sensing of intestinal cells.
Deschemin JC, Noordine ML, Remot A, Willemetz A, Afif C, Canonne-Hergaux F, Langella P, Karim Z, Vaulont S, Thomas M, Nicolas G.
FASEB J 2016, 30:252-61.
Decreased Bone Formation Explains Osteoporosis in a Genetic Mouse Model of Hemochromatosis.
Doyard M, Chappard D, Leroyer P, Roth MP, Loréal O, Guggenbuhl P.
PLoS One 2016, 11:e0148292.
Targeting iron-mediated retinal degeneration by local delivery of transferrin.
Picard E, Le Rouzic Q, Oudar A, Berdugo M, El Sanharawi M, Andrieu-Soler C, Naud MC, Jonet L, Latour C, Klein C, Galiacy S, Malecaze F, Coppin H, Roth MP, Jeanny JC, Courtois Y, Behar-Cohen F.
Free Radic Biol Med 2015, 89:1105-21.
Genome-wide association study identifies TF as a significant modifier gene of iron metabolism in HFE hemochromatosis.
de Tayrac M, Roth MP, Jouanolle AM, Coppin H, le Gac G, Piperno A, Férec C, Pelucchi S, Scotet V, Bardou-Jacquet E, Ropert M, Bouvet R, Génin E, Mosser J, Deugnier Y.
J Hepatol 2015, 62:664-72.
Testosterone perturbs systemic iron balance through activation of epidermal growth factor receptor signaling in the liver and repression of hepcidin.
Latour C, Kautz L, Besson-Fournier C, Island ML, Canonne-Hergaux F, Loréal O, Ganz T, Coppin H, Roth MP.
Hepatology 2014, 59:683-94.
Glycol-split nonanticoagulant heparins are inhibitors of hepcidin expression in vitro and in vivo.
Poli M, Asperti M, Naggi A, Campostrini N, Girelli D, Corbella M, Benzi M, Besson-Fournier C, Coppin H, Maccarinelli F, Finazzi D, Arosio P.
Blood 2014, 123:1564-73.
Induction of activin B by inflammatory stimuli up-regulates expression of the iron-regulatory peptide hepcidin through Smad1/5/8 signaling.
Besson-Fournier C, Latour C, Kautz L, Bertrand J, Ganz T, Roth MP, Coppin H.
Blood 2012, 120:431-9.
Iron overload induces BMP6 expression in the liver but not in the duodenum.
Kautz L, Besson-Fournier C, Meynard D, Latour C, Roth MP, Coppin H.
Haematologica 2011, 96:199-203.
BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression.
Kautz L, Meynard D, Besson-Fournier C, Darnaud V, Al Saati T, Coppin H, Roth MP.
Blood 2009, 114:2515-20.
Lack of the bone morphogenetic protein BMP6 induces massive iron overload.
Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth MP.
Nat Genet 2009, 41:478-81.
Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver.
Kautz L, Meynard D, Monnier A, Darnaud V, Bouvet R, Wang RH, Deng C, Vaulont S, Mosser J, Coppin H, Roth MP.
Blood 2008, 112:1503-9.
Traeger L, Gallitz I, Sekhri R, Bäumer N, Kuhlmann T, Kemming C, Holtkamp M, Müller JC, Karst U, Canonne-Hergaux F, Muckenthaler MU, Bloch DB, Olschewski A, Bartnikas TB, Steinbicker AU.
Free Radic Biol Med 2018, 129:127-137.
The histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity.
Bricambert J, Alves-Guerra MC, Esteves P, Prip-Buus C, Bertrand-Michel J, Guillou H, Chang CJ, Vander Wal MN, Canonne-Hergaux F, Mathurin P, Raverdy V, Pattou F, Girard J, Postic C, Dentin R.
Nat Commun 2018, 29:2092.
Deletion of BMP6 worsens the phenotype of HJV-deficient mice and attenuates hepcidin levels reached after LPS challenge.
Latour C, Besson-Fournier C, Gourbeyre O, Meynard D, Roth MP, Coppin H.
Blood 2017, 130:2339-2343.
Hepcidin upregulation by inflammation is independent of Smad1/5/8 signaling by activin B.
Besson-Fournier C, Gineste A, Latour C, Gourbeyre O, Meynard D, Martin P, Oswald E, Coppin H, Roth MP.
Blood 2017, 129:533-536.
Erythroferrone contributes to hepcidin repression in a mouse model of malarial anemia.
Latour C, Wlodarczyk MF, Jung G, Gineste A, Blanchard N, Ganz T, Roth MP, Coppin H, Kautz L.
Haematologica 2017, 102:60-68.
Iron- and Hepcidin-Independent Downregulation of the Iron Exporter Ferroportin in Macrophages during Salmonella Infection.
Willemetz A, Beatty S, Richer E, Rubio A, Auriac A, Milkereit RJ, Thibaudeau O, Vaulont S, Malo D, Canonne-Hergaux F.
Front Immunol 2017, 8:498.
Acute loss of the hepatic endo-lysosomal system in vivo causes compensatory changes in iron homeostasis.
Metzendorf C, Zeigerer A, Seifert S, Sparla R, Najafi B, Canonne-Hergaux F, Zerial M, Muckenthaler MU.
Sci Rep 2017, 7:4023.
Activin inhibition limits early innate immune response in rat kidney allografts-a pilot study.
Palin NK, Savikko J, Pasternack A, Rintala JM, Kalra B, Mistry S, Kumar A, Roth MP, Helin H, Ritvos O.
Transpl Int 2017, 30:96-107.
Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice.
Nai A, Rubio A, Campanella A, Gourbeyre O, Artuso I, Bordini J, Gineste A, Latour C, Besson-Fournier C, Lin HY, Coppin H, Roth MP, Camaschella C, Silvestri L, Meynard D.
Blood 2016, 127:2327-36.
Differing impact of the deletion of hemochromatosis-associated molecules HFE and transferrin receptor-2 on the iron phenotype of mice lacking bone morphogenetic protein 6 or hemojuvelin.
Latour C, Besson-Fournier C, Meynard D, Silvestri L, Gourbeyre O, Aguilar-Martinez P, Schmidt PJ, Fleming MD, Roth MP, Coppin H.
Hepatology 2016, 63:126-37.
Further support for the association of GNPAT variant rs11558492 with severe iron overload in hemochromatosis.
Besson-Fournier C, Martinez M, Vinel JP, Aguilar-Martinez P, Coppin H, Roth MP.
Hepatology 2016, 63:2054-5.
Evidence for IL-6/STAT3-independent induction of lipocalin-2 in the liver of mice infected with Escherichia coli.
Gineste A, Martin P, Oswald E, Coppin H, Roth MP.
Hepatology 2016, 63:673-4.
Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance.
Popineau L, Morzyglod L, Carré N, Caüzac M, Bossard P, Prip-Buus C, Lenoir V, Ragazzon B, Fauveau V, Robert L, Guilmeau S, Postic C, Komatsu M, Canonne-Hergaux F, Guillou H, Burnol AF.
Mol Cell Biol 2016, 36:2168-81.
Iron gene expression profile in atherogenic Mox macrophages.
Marques L, Negre-Salvayre A, Costa L, Canonne-Hergaux F.
Biochim Biophys Acta 2016, 1862:1137-46.
The microbiota shifts the iron sensing of intestinal cells.
Deschemin JC, Noordine ML, Remot A, Willemetz A, Afif C, Canonne-Hergaux F, Langella P, Karim Z, Vaulont S, Thomas M, Nicolas G.
FASEB J 2016, 30:252-61.
Decreased Bone Formation Explains Osteoporosis in a Genetic Mouse Model of Hemochromatosis.
Doyard M, Chappard D, Leroyer P, Roth MP, Loréal O, Guggenbuhl P.
PLoS One 2016, 11:e0148292.
Targeting iron-mediated retinal degeneration by local delivery of transferrin.
Picard E, Le Rouzic Q, Oudar A, Berdugo M, El Sanharawi M, Andrieu-Soler C, Naud MC, Jonet L, Latour C, Klein C, Galiacy S, Malecaze F, Coppin H, Roth MP, Jeanny JC, Courtois Y, Behar-Cohen F.
Free Radic Biol Med 2015, 89:1105-21.
Genome-wide association study identifies TF as a significant modifier gene of iron metabolism in HFE hemochromatosis.
de Tayrac M, Roth MP, Jouanolle AM, Coppin H, le Gac G, Piperno A, Férec C, Pelucchi S, Scotet V, Bardou-Jacquet E, Ropert M, Bouvet R, Génin E, Mosser J, Deugnier Y.
J Hepatol 2015, 62:664-72.
Testosterone perturbs systemic iron balance through activation of epidermal growth factor receptor signaling in the liver and repression of hepcidin.
Latour C, Kautz L, Besson-Fournier C, Island ML, Canonne-Hergaux F, Loréal O, Ganz T, Coppin H, Roth MP.
Hepatology 2014, 59:683-94.
Glycol-split nonanticoagulant heparins are inhibitors of hepcidin expression in vitro and in vivo.
Poli M, Asperti M, Naggi A, Campostrini N, Girelli D, Corbella M, Benzi M, Besson-Fournier C, Coppin H, Maccarinelli F, Finazzi D, Arosio P.
Blood 2014, 123:1564-73.
Induction of activin B by inflammatory stimuli up-regulates expression of the iron-regulatory peptide hepcidin through Smad1/5/8 signaling.
Besson-Fournier C, Latour C, Kautz L, Bertrand J, Ganz T, Roth MP, Coppin H.
Blood 2012, 120:431-9.
Iron overload induces BMP6 expression in the liver but not in the duodenum.
Kautz L, Besson-Fournier C, Meynard D, Latour C, Roth MP, Coppin H.
Haematologica 2011, 96:199-203.
BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression.
Kautz L, Meynard D, Besson-Fournier C, Darnaud V, Al Saati T, Coppin H, Roth MP.
Blood 2009, 114:2515-20.
Lack of the bone morphogenetic protein BMP6 induces massive iron overload.
Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth MP.
Nat Genet 2009, 41:478-81.
Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver.
Kautz L, Meynard D, Monnier A, Darnaud V, Bouvet R, Wang RH, Deng C, Vaulont S, Mosser J, Coppin H, Roth MP.
Blood 2008, 112:1503-9.
