Réunion annuelle de pathologie digestive. Iron Metabolism

Transcription

1 Réunion annuelle de pathologie digestive Hopital Cochin-Hôtel Dieu Iron Metabolism 3 Février 2012 Sophie Vaulont Iron metabolism endosome steap IRP Pigeon et ferritin al., 2001, JBC, 276, use Ferritin 1

2 10-20 mg Iron metabolism peptide signal Furin cleavage site pro region Hepc-25Aa DTHFPICIFCCGCCHRSKCGMCCKT Ferritin mg Iron handling in enterocytes and macrophages apical surface basolateral surface Ferritin Fe 3+ Fe 2+ heme Dcytb HCP ferroportin ferritin hephaestin Fe 3+ Fe 2+ enterocyte iron-transferrin 2

3 10-20 mg Iron handling in enterocytes and macrophages apical surface basolateral surface Ferritin Fe 3+ Fe 2+ heme Dcytb Hb HCP ferritin heme ferroportin hephaestin Fe 3+ Fe 2+ enterocyte ferroportin iron-transferrin CP APO- HOLO- Mode of action of ferroportin enterocyte RBC ferroportin macrophage Nemeth et al., Science

4 How kidney handles iron Exact localisation Fp 78 kda Reabsoprtion along the proximal tubule Only 1% of filtred iron is found in the urines! Nephrotic kidney diseases: iron accumulation in PT lysosomes due to increased reabsorption Toni-Debré-Fanconi syndromes: fold of urinary due to a general defect of renal PT transport systems Form Craig P. Smith, Frank Thévenod, BBA, 2009 How brain handles iron Epithelium (choroid plexus) Receptor-mediated transcytosis Dopaminergic neurotransmitters Cp/APP APP tim2 From Benarroch E, Clinical Implications of Neuroscience Research,

5 .GESTATION.ADOLESCENCE Hepcidin : the sensor of the body iron demands.low Iron stores.erythropoiesis.hypoxia Hepcidin : the sensor of the body iron demands 5

6 .Elevated Iron stores Park.Suppressed et al., 2001, erythropoiesis JBC, 276, Hepcidin : the sensor of the body iron demands Hepcidin and innate immunity.inflammation/infection Anemia of Inflammation (ACD) Infections Viral infections including HIV Bacterial Parasitic Fungal Helminth Malignancies Haematologic Solid tumor Autoimmune Rheumatoid arthritis Systemic lupus erythematosus and connective tissue diseases Vasculitis Inflammatory bowel disease Chronic kidney disease and inflammation 6

7 .Low Iron stores.erythropoiesis.hypoxia.elevated Iron stores.supressed erythropoiesis.inflammation/infection Mechanisms of regulation Mechanisms of regulation Inflammation JAK cytokines Stat3.Il6.Il22 erythropoiesis EPO Impairment of erythrocyte progenitor formation Iron retention within the macrophages Inadequate formation and function oferythropoietin 7

8 Mechanisms of regulation Iron overload Iron state Iron deficiency/ anemia/hypoxia Mechanisms of regulation Iron overload Iron state R2 Hfe BMP6 Smad4 Hereditary Hemochromatosis increased intestinal iron absoprtion transferrin saturation >45% increased ferritin Iron accumulation -liver (cirrhosis and cancer) -pancreas (diabetes) -heart (cardiomyopathy) -osteo-articular system (arthropathies) Due to deficiency 8

9 Mechanisms of regulation Iron deficiency/ anemia/hypoxia Erythropoietic activity EPO Iron state SP Serine Protease Matriptase 2 Mechanisms of regulation Iron deficiency/ anemia/hypoxia Iron state SP Human mutations in TMPRSS6 IRIDA Iron Refractory Iron Deficiency Anemia 9

10 Hepcidin Hepcidin is an hyposideremic hormone Expressed mainly in hepatocytes BUT Hepcidin Stomac parietal gastric acid Biliary sytem Lymphocytes Adipose tissue Kidney Pancreas Brain Mononuclear Blood Macrophages stress-inducible peptide iron, TNFα inflammation Infection/inflammation TLR5 agonist flagellin (IL-6-dependent), Candida albicans (IL-6-independent) H1N1 viral infection and plasmodium (TLR-4 Pseudomonas & Streptococcus and TLR 2 Borrelia burgdorfer) Mammary epithelial Breast Cancer Progression and Prognosis Hepcidin Hepcidin is an hyposideremic hormone Expressed mainly in hepatocytes BUT Inhibiting duodenal iron absorption, macrophagic iron release via the degradation of ferroportin In red: human mutations that result in -resistant ferroportin disease ferroportin 10

11 Hepcidin Hepcidin is an hyposideremic hormone Expressed mainly in hepatocytes BUT Inhibiting duodenal iron absorption, macrophagic iron release via the degradation of ferroportin Hepcidin is regulated by.iron status BMP/SMAD.inflammation Kroot et al CC 2011 Hepcidin is deregulated in iron disorders : iron homeostasis Hereditary Hemochromatosis Hfe (80%) Rtf2 HJV Hepcidin Secondary iron overload Hematological disorders (thalassemia) Liver disease Alcoholic Hepatitis C viral Anemia of inflammation Infectious/inflammatory Malignancies Immunologic Traumatic Iron refractory iron-deficiency anemia Matriptase 2 11

12 Hepcidin inhibition BMP6 inhibitors SerineProtease TMPRSS6 Agonists/activators HJV inhibitors HJV s ROCHE/XENON FERRUMAX HJV-Fc fusion protein PHD inhibitors: Stabilisation of HIF: increase of EPO AMGEN O 2 Iron PHD OH VHL HIF OH FIBROGEN FG-2216 & FG-4592 small molecules, orally active, in clinical development for the treatment of anemia Hepcidin activation BMP6 agonists Serine Protease TMPRSS6 antagonists Hepcidin agonists Mini Intinsic LifeScience 12

13 Bichat hospital, Paris Carole Beaumont Bernard Grandchamp Institut Cochin, Paris Carole Peyssonnaux Pavle Matak Maria Mastroginannaki Lydie Viatte Gaël Nicolas Anne Lenoir Guillemette Ramey Bomee Chung Jean Christophe Deschemin CNRS,GIF François Canonne-Hergaux Duke University School of Medicine Nancy Andrews INSERM 564, Angers Hugues Gascan Josy Froger Institut Cochin, Paris Frédérique Verdier Patrick Mayeux Saint Peres, Paris Isabelle Artaud Marie Agnès Sarie BIBLIOGRAPHY Iron sensing and signalling. Evstatiev R, Gasche C. Gut Oct 19. On line Hepcidin in human iron disorders: diagnostic implications. Kroot JJ, Tjalsma H, Fleming RE, Swinkels DW. Clin Chem Dec;57(12): Hepcidin and iron regulation, 10 years later. Ganz T. Blood Apr 28;117(17): Molecular basis of iron-loading disorders. Darshan D, Frazer DM, Anderson GJ. Expert Rev Mol Med Nov 8;12:e36 Two to tango: regulation of Mammalian iron metabolism. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Cell Jul 9;142(1):24-38 Hepcidin, the iron watcher. Viatte L, Vaulont S. Biochimie Oct;91(10):