DOCSLIB.ORG

The Immunomodulatory Role of Epidermal Hepcidin in Infectious Condition

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Immunomodulatory Role of Epidermal Hepcidin in Infectious Condition Université Paris Descartes École doctorale : Bio Sorbonne Paris Cité Institut Cochin, Hypoxia and iron homeostasis team The immunomodulatory role of epidermal hepcidin in infectious condition Par Mariangela MALERBA Thèse de doctorat de Physiopathologie Dirigée par Carole PEYSSONNAUX Présentée et soutenue publiquement le 25/09/2018 Devant un jury composé de : Dr. Carole PEYSSONNAUX Directeur de thèse Pr. Sylvie CHOLLET-MARTIN Rapporteur Dr. François CANONNE-HERGAUX Rapporteur Pr. Selim ARACTINGI Examinateur Dr. Agnès FOUET Membre invité 1 Contents ABSTRACT .......................................................................................................................................................... 6 INTRODUCTION ................................................................................................................................................. 8 HEPCIDIN ............................................................................................................................................... 9 1.1. Hepcidin: synthesis and structure ................................................................................................. 9 1.2. Hepcidin antimicrobial function .................................................................................................. 11 1.3. Hepcidin: iron regulatory hormone ............................................................................................. 12 1.3.1. Iron metabolism ...................................................................................................................... 12 1.3.2. Regulation of the iron homeostasis ......................................................................................... 16 1.4. Hepcidin/infection axis ................................................................................................................ 17 1.5. Hepcidin regulation ..................................................................................................................... 21 1.6. Extra-hepatic hepcidin and other roles. ...................................................................................... 25 2. SKIN ...................................................................................................................................................... 29 2.1. Mammalian skin architecture ...................................................................................................... 29 2.2. Skin Immunity .............................................................................................................................. 35 3. NEUTROPHIL ........................................................................................................................................ 47 3.1. Neutrophil production and bone marrow egress ........................................................................ 47 3.2. Neutrophils in tissue .................................................................................................................... 50 3.3. Chemoattractant molecules: the chemokine family ................................................................... 53 3.4. Role of neutrophils in fighting infection ...................................................................................... 55 4. GAS ...................................................................................................................................................... 63 4.1. Epidemiology of GAS infection .................................................................................................... 63 4.2. M1T1 : GAS invasive strain .......................................................................................................... 66 4.3. GAS-phagocyte fighting ............................................................................................................... 70 4.4. GAS-keratinocyte fighting ............................................................................................................ 73 4.5. GAS iron metabolism ................................................................................................................... 74 THE AIM OF THE STUDY ................................................................................................................................... 75 RESULTS ........................................................................................................................................................... 77 1. Hepcidin shares structural similarities with IL8 and displays neutrophil chemoattractant properties. 78 Hepcidin is expressed in the epidermis ............................................................................................... 85 Epidermal hepcidin has a protective role against GAS infection ........................................................ 88 Hepcidin has no antimicrobial effect against GAS in vitro and does not influence keratinocyte antimicrobial functions. ............................................................................................................................... 92 Hamp1 Δker mice do not display epidermal iron accumulation ......................................................... 93 Hepcidin modulates keratinocyte immune response ......................................................................... 96 Hepcidin- mediated CXCL1 production protects against GAS infection. ............................................. 99 2 Hepcidin is resistant to SpyCEP cleavage .......................................................................................... 101 Hepcidin subcutaneous injections have a therapeutic potential against GAS infection ................... 104 SUPPLEMENTARY FIGURES ............................................................................................................ 106 MATERIALS AND METHODS ........................................................................................................................... 110 DISCUSSION ................................................................................................................................................... 117 New chemoattractant role of hepcidin. ............................................................................................ 118 Hepcidin is expressed in the skin in pathophysiological conditions .................................................. 120 Keratinocyte- derived hepcidin has an immunomodulatory role during infection ........................... 122 Hepcidin as a therapeutic agent ........................................................................................................ 127 Conclusion and highlights .................................................................................................................. 130 BIBLIOGRAPHY ............................................................................................................................................... 131 ANNEXES ........................................................................................................................................................ 158 Epidermal hepcidin prevents systemic bacterial spreading in a Group A streptococcus-induced necrotizing soft tissue infection model ..................................................................................................... 159 Methods for treating gram positive bacterial infection .................................................................... 176 3 TABLE OF ABBREVIATIONS Aa amino acid IRP iron regulatory protein RLR RIG-like helicases AI anaemia of inflammation JAK Janus activated kinases ROS reactive oxygen species AMP antimicrobial peptide KRT keratin SC subcutaneous APC antigen presenting cell LF lactoferrin Scl1 streptococcus collagen-like ARF acute rheumatic fever LFA1 lymphocyte function- ScpA streptococcal C5a peptidase associated antigen1 A BM basement membrane LIP labile iron pool Sda1 Sterptococcal DNAse 1 BMP bone morphogenetic protein LPS lipopolysaccharide Shp streptococcal heme binding CLR C-type lectin receptor protein LTA lipoteicoic acid CXCL CXC-chemokine ligand Shr streptococcal heme protein MMP8/9 metrix metalloprotease receptor CXCR CXC-chemokine receptor 8/9 Ska1 Streptokinase 1 DAMP damage associated MPO myeloperoxidase molecular pattern SLO streptolysin O NE Neutrophil elastase DC dendritic cell SLS streptolysin S NET neutrophil extracellular trap dcytB duodenal cytochrome B sodA superoxide-detoxifying NLR NOD like receptor DMT1 Divalent metal transporter enzyme A 1 NoxA NADPH oxidase A SpeA/B Streptococcal Pyrogenic EPO erythropoiesis NRAMP1/2 natural resistance Exotoxin A/B associated macrophage protein Spy CEP streptococcus pyogenes fMLP N-Formylmethionyl- 1/2 leucyl-phenylalanine cell envelope protease NTBI non transferrin bound iron FPN ferroportin Sse Streptococcal esterase OH heme oxygenase GAS Group A streptococcus STAT signal transducers and PAMP pathogen associated activators of transcription GCPR G protein coupled receptor molecular pattern STSS streptococcal toxic shock G-CSF Granulocyte colony PDA 4 protein arginine deiminase syndrome stimulating factor type 4 Tf transferrin GM-CSF Granulocyte- PGN peptidoglycan macrophage colony-stimulating TfR1/2 transferrin receptor 1/2 PMN polymorphonuclear TJ tight junction HA hyaluronan capsule leukocyte TLR toll-like receptor HCP1 heme carrier protein PRR pattern recognition receptor TMPRSS6 matriptase HF hair follicle PSGL1 P-selectin glycoprotein HH hereditary hemochromatosis ligand 1 WT wild type HIFs hypoxia inducible factors
Load more

Recommended publications
  • How Severe Anaemia Might Influence the Risk of Invasive Bacterial
    International Journal of Molecular Sciences Hypothesis How Severe Anaemia Might Influence the Risk of Invasive Bacterial Infections in African Children Kelvin M. Abuga 1,* , John Muthii Muriuki 1 , Thomas N. Williams 1,2,3 and Sarah H. Atkinson 1,2,4,* 1 Kenya Medical Research Institute (KEMRI) Center for Geographical Medicine Research-Coast, KEMRI-Wellcome Trust Research Programme, Kilifi P.O. Box 230-80108, Kenya; [email protected] (J.M.M.); [email protected] (T.N.W.) 2 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK 3 Department of Infectious Diseases and Institute of Global Health Innovation, Imperial College, London W2 1NY, UK 4 Department of Paediatrics, University of Oxford, Oxford OX3 9DU, UK * Correspondence: [email protected] (K.M.A.); [email protected] (S.H.A.) Received: 4 August 2020; Accepted: 15 September 2020; Published: 22 September 2020 Abstract: Severe anaemia and invasive bacterial infections are common causes of childhood sickness and death in sub-Saharan Africa. Accumulating evidence suggests that severely anaemic African children may have a higher risk of invasive bacterial infections. However, the mechanisms underlying this association remain poorly described. Severe anaemia is characterized by increased haemolysis, erythropoietic drive, gut permeability, and disruption of immune regulatory systems. These pathways are associated with dysregulation of iron homeostasis, including the downregulation of the hepatic hormone hepcidin. Increased haemolysis and low hepcidin levels potentially increase plasma, tissue and intracellular iron levels. Pathogenic bacteria require iron and/or haem to proliferate and have evolved numerous strategies to acquire labile and protein-bound iron/haem.
    [Show full text]
  • UNIVERSITY of CALIFORNIA Los Angeles the Role
    UNIVERSITY OF CALIFORNIA Los Angeles The role of iron and hepcidin in infection A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Molecular, Cellular and Integrative Physiology by Debora Chavdarova Stefanova 2018 ABSTRACT OF THE DISSERTATION The role of iron and hepcidin in infection by Debora Chavdarova Stefanova Doctor of Philosophy in Molecular, Cellular and Integrative Physiology University of California, Los Angeles, 2018 Professor Elizabeta Nemeth, Chair Iron is an essential trace nutrient for both higher organisms and bacteria. Consequently, hosts have evolved to sequester iron during infection, while pathogens have developed multiple iron acquisition systems to access iron pools in the host. Hepcidin, the master iron-regulatory hormone, is induced by inflammatory cytokines early during infections. Hepcidin lowers extracellular iron concentration by binding to and inhibiting the cellular iron exporter ferroportin. Using structural modeling and site-directed mutagenesis, we analyzed the structural basis of ferroportin interaction with hepcidin. Hepcidin induction by inflammation causes a rapid decrease in plasma iron concentration (hypoferremia) accompanied by iron retention within target cells (macrophages, enterocytes, hepatocytes). This response to infection is highly conserved during vertebrate evolution. In the main part of this thesis, we show that hepcidin is essential for protection against extracellular Gram-negative bacterium Yersinia enterocolitica. At the ii same inocula, hepcidin-deficient mice suffer 100% mortality while WT mice survive disease-free. We determine that it is the spontaneous iron overload of hepcidin-deficient mice that promotes susceptibility to infection. We find that hepcidin is not universally protective and plays no role in catheter-associated Staphylococcus aureus infection or in macrophage-tropic Mycobacterium tuberculosis.
    [Show full text]
  • PUBLICATION of the SUPERIOR HEALTH COUNCIL No. 8672
    E / 110920 PUBLICATION OF THE SUPERIOR HEALTH COUNCIL No. 8672 Acceptance of HFE haemochromatosis gene mutation carriers as blood donors 9 January 2013 1. INTRODUCTION AND ISSUE For quite a while now, a controversy has raged amongst patients and carriers of the haemochromatosis mutation, general practitioners and blood establishments over whether or not haemochromatosis patients should be allowed to give blood. At the moment, most blood establishments reject haemochromatosis patients as donors of whole blood and blood components. In Belgium, this approach is based on two provisions of the Act of 5 July 1994 regarding blood and blood products of human origin (modified by the Royal Decree of 1 February 2005) according to which blood and blood products for transfusion purposes shall only be collected from volunteer donors who shall receive no compensation in return. Donations from haemochromatosis patients (probably) fail to meet the disinterested and voluntary donation requirement, as they are carried out for therapeutic purposes. It follows that there is a risk that the donor will withhold information that is liable to stand in the way of their giving blood. The exclusion criteria for potential donors mentioned in the appendix of the Act referred to above also include metabolic disorders. Haemochromatosis can be taken to be such a disorder. In a previous advisory report, the Superior Health Council (SHC, 2004) emphasised the paramount importance of the altruistic nature of blood donations, mainly in order to ensure the safety of the blood components. At the time, a request to depart from this principle in the case of haemochromatosis patients was declined.
    [Show full text]