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Human S100A8 and S100A9 Scavenge Pro-Inflammatory Hypohalous Acids in Disease

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Human S100A8 and S100A9 Scavenge Pro-Inflammatory Hypohalous Acids in Disease Human S100A8 and S100A9 Scavenge Pro-inflammatory Hypohalous Acids in Disease by Lincoln Henry Gomes A thesis submitted in fulfillment of the requirements for the degree of Doctor of Philosophy Faculty of Medicine The University of New South Wales 2012 THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: Gomes First name: Lincoln Other name/s: Henry Abbreviation for degree as given in the University calendar: PhD School: Medical Sciences Faculty: Medicine Title: S100A8 and S100A9 scavenge pro-inflammatory hypohalous acids in disease Abstract 350 words maximum: (PLEASE TYPE) S100A8, S100A9 and S100A12 are generally considered pro-inflammatory proteins because their expression is elevated in chronic inflammatory disorders. Hypohalous acids generated by activated phagocytes are scavenged by murine S100A8 and S100A9, suggesting a protective role in oxidative stress, but effects on human recombinant S100A8 and S100A9 are undefined. Hypohalous acids at low molar ratios (1:1) promoted structural changes in human S100A8 and S100A9 in vitro, generating two novel post- translational modifications on Cys42 in S100A8, defined as oxathiazolidine-oxide and dioxide. Particular methionine residues in S100A9 were also modified. S100A8 and S100A9 are increased in respiratory diseases in which reactive oxygen species are implicated and anti-oxidant mechanisms compromised. Oxidized S100A8 (oxS100A8) was prominent in asthmatic lung and significantly elevated in sputum, compared to controls, whereas S100A8 or S100A9 levels were not. Monomeric oxS100A8 was the major component in asthmatic sputum; modifications were similar to those generated by hypochlorous acid (HOCl) in vitro. Oxidized Met63/81/94 were variously present in S100A9 from asthmatic sputum, only oxidized Met63 was seen in control sputum. oxS100A8 and oxS100A9 did not form heterocomplexes and neutrophil adhesion to fibronectin, properties typical of the native complex, and antimicrobial activity was significantly compromised. Inflammation is associated with increased risk of cardiovascular disease in chronic autoimmune diseases such as systemic lupus erythematosus (SLE) and with asthma. Serum levels of S100A8, S100A9 and S100A8/A9 were similar in patients with SLE and controls. Native and oxS100A8 were not apparent in Western blots of serum, and were located in HDL, possibly due to interaction with ApoAI. Carotid artery extracts indicated oxidant scavenging by S100A8 and S100A9. S100A8 protection of lipid-free ApoAI against oxidation by HOCl was Cys42-dependent. S100A8 and S100A9 reduced generation of hypochlorite-oxidized proteins in endothelial cells, suggesting a protective role for these proteins in the vasculature. Results have broad implications in diseases where hypohalous acid oxidants are generated and support the notion that oxidant scavenging and subsequent post-translational modifications are functionally important, emphasizing a role for S100A8 and S100A9 in redox homeostasis in inflammation. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). …………………………………………………………… ……………………………………..……………… ……….……………………...…….… Signature Witness Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: THIS SHEET IS TO BE GLUED TO THE INSIDE FRONT COVER OF THE THESIS ii ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date …………………………………………….............. iii Dedicated to Shirley Meades and Ann Gomes. You have given me many precious memories and inspired me to live a meaningful life. You will never be forgotten. iv TABLE OF CONTENTS LIST OF FIGURES……………………………………………………………………xiii LIST OF TABLES……………………………………………………………………..xvi ABBREVIATIONS………………………………………………………...................xviii ACKNOWLEDGEMENTS………………………………………………………...xxviii PUBLISHED WORK AND AWARDS FROM THIS THESIS…………………....xxix ABSTRACT…………………………………………………………………………...xxxi 1: INTRODUCTION……………………………………………………………………..1 1.1 THE S100 PROTEIN FAMILY……………………………………………….1 1.1.1 NOMENCLATURE…………………………………………………..1 1.1.2 S100 GENE STRUCTURE…………………………………………..5 1.1.2.1 Chromosome location……………………………………..5 1.1.2.2 Genomic organization and S100 isoforms………………...8 1.1.2.3 Phylogeny and evolution of S100 proteins………………10 1.1.3 S100 PROTEIN STRUCTURE………..………..…………………..16 1.1.3.1 EF-hands………..………..………..……………………...16 1.1.3.2 Zinc and copper binding………..………..……………….18 1.1.3.3 Dimer formation and its effects on function……………..19 1.1.4 EXPRESSION OF S100 PROTEINS………..………..…………….22 1.1.4.1 S100 expression profiles………..………………………..22 1.1.4.2 S100 protein and mRNA induction by extracellular stimuli…………………………………………………………….24 1.2 FUNCTIONS OF S100 PROTEINS………..………..………..……………..25 1.2.1 INTRACELLULAR FUNCTIONS………..………..……………….25 1.2.1.1 Cell growth and differentiation………..………..………..25 1.2.1.2 Regulation of calcium homeostasis………..……………..26 1.2.1.3 Regulation of enzyme activities………..………………...26 1.2.1.4 Regulation of protein phosphorylation.…………………..28 1.2.1.5 Interaction with cytoskeletal components………………..29 1.2.1.6 Interaction with transcription factors…………………….33 1.2.2 EXTRACELLULAR FUNCTIONS OF S100 PROTEINS…………..33 1.2.2.1 Receptors for S100 proteins………..…………………….38 1.2.2.2 Neurotrophic and neurotoxic effects………..……………39 v 1.2.2.3 Apoptotic properties………..………..…………………...39 1.2.2.4 Mitogenic activities………..………..……………………40 1.2.2.5 Host defense against infection………..…………………..40 1.2.2.6 Chemotactic activity………..………..…………………...41 1.2.3 S100 PROTEINS AND HUMAN DISEASE………..……………….42 1.3 INFLAMMATION-ASSOCIATED S100 PROTEINS……………………...45 1.3.1 S100A8 AND S100A9………..………..………..………..…………45 1.3.1.1 Structure………..………..………..………..…………….45 1.3.1.2 Regulation of S100A8 and S100A9………..…………….48 1.3.1.3 Expression of S100A8 and S100A9………..…………….49 1.3.2 REGULATION AND EXPRESSION OF S100A12…………………55 1.3.3 CALGRANULINS IN DISEASE………..………..…………………56 1.3.3.1 Expression in infectious diseases………..……………….59 1.3.3.2 Respiratory diseases………..………..…………………...60 1.3.3.3 Expression in vascular diseases………..…………………61 1.3.3.4 Expression in autoimmune diseases………..…………….62 1.3.3.5 Expression in cancer………..………..………..…………63 1.3.3.6 Expression in skin diseases………..………..……………65 1.3.4 DIFFERENTIATION AND DEVELOPMENT………..……………66 1.3.4.1 S100A8 and S100A9 in development………..…………..66 1.3.4.2 S100A8 and S100A9 in differentiation………..…………67 1.3.5 INTRACELLULAR FUNCTIONS OF CALGRANULINS………….68 1.3.5.1 Modulation of intracellular calcium………..…………….68 1.3.5.2 Regulation of enzyme activity………..………..………....69 1.3.5.3 Fatty acid metabolism and transport………..……………69 1.3.5.4 Regulation of NADPH oxidase activity………..………...70 1.3.5.5 Regulation of cytoskeletal dynamics.………….…………71 1.3.5.6 Antimicrobial and anti-invasive activity………………....71 1.3.5.7 Intracellular functions of S100A12………..……………..73 1.3.6 EXTRACELLULAR FUNCTIONS OF CALGRANULINS…………74 1.3.6.1 Extracellular functions of calgranulins…………………..74 1.3.6.2 Secretion of the calgranulins………..………..…………..78 1.3.6.3 Phagocyte migration………..………..………..………….78 1.3.6.4 Mast cell function………..………..………..………..…...81 vi 1.3.6.5 Regulation of MMPs………..………..………..…………82 1.3.6.6 Anti-nociceptive activity………..………..………..……..83 1.3.6.7 Antimicrobial and anti-invasive activity………..………..83 1.3.6.8 Apoptosis………..………..………..………..……………86 1.3.6.9 Studies with S100A8 (S100A8-/-) and S100A9 knockout (S100A9-/-) mice ………..………..………..………..……………86 1.3.6.10 Functional consequences of S100A9 deficiency………..87 1.3.7 EXTRACELLULAR FUNCTIONS OF S100A12………..………….91 1.3.8 RECEPTORS FOR S100A8, S100A9 AND S100A12………..……..94 1.3.8.1 Glycosaminoglycans………..………..………..…………94 1.3.8.2 CD36………..………..………..………..………..………95 1.3.8.3 TLR-4………..………..………..………..………..……...95 1.3.8.4 RAGE………..………..………..………..………..……...97 1.3.9 S100A8, S100A9 AND S100A12 AS DAMAGE-ASSOCIATED MOLECULAR PATTERNS (DAMPs)………..………..…………………99 1.4 CALGRANULINS
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