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The Expression and Function of Leukocyte Immunoglobulin-Like Receptor A3: Potential Implication in Multiple Sclerosis

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The Expression and Function of Leukocyte Immunoglobulin-Like Receptor A3: Potential Implication in Multiple Sclerosis Hongyan An A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy School of Medical Sciences Faculty of Medicine The University of New South Wales March 2016 THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: An First name: Hongyan Other name/s: Abbreviation for degree as given in the University calendar: PhD School: School of Medical Sciences Faculty: Medicine Title: The expression and function of leukocyte immunoglobulin-like receptor A3: potential implication in multiple sclerosis Abstract LILRA3 is a soluble protein belonging to a family of highly homologous activating and inhibitory receptors mainly expressed on leukocytes and increasingly recognised as key immunoregulatory molecules in the immune system. LILRA3 gene deletion has been associated with multiple sclerosis (MS) susceptibility, but results are not consistent among different study populations. In our study, we found no link between LILRA3 gene deletion and MS susceptibility in a North American cohort. Instead, serum LILRA3 level was significantly increased in patients with MS and strongly associated with disease severity, suggesting that LILRA3 protein may play a role in disease progression. Indeed, we showed that elevated serum LILRA3 had a positive correlation with better clinical outcomes and anti-inflammatory cytokine IL-10, suggesting an anti-inflammatory role of LILRA3 in MS. Importantly, this study also suggested a potential use for measuring serum LILRA3 levels as a biomarker for disease severity in MS. The functions of LILRA3 in MS remain unknown due to the limited knowledge of its ligands. This thesis showed that Nogo 66, a potent neurite outgrowth inhibitor, is a new functional ligand for LILRA3. We showed that the high affinity binding of LILRA3 with Nogo 66 blocked Nogo 66-mediated inhibition of neurite outgrowth and promoted synapse formation in primary cortical neurons. In addition, LILRA3 is able to block Nogo 66-mediated suppression of MAPK signalling in primary cortical neurons. All these results suggested that LILRA3 acts as a broad antagonist to block the interactions between Nogo 66 and its neuronal receptors and their subsequent inhibitory effects and thus promote neuroregeneration. Despite the novel anti-inflammatory and neuroregenerative roles of LILRA3 in MS, little is known about the quaternary structure of LILRA3, which may be crucial for its ligand binding and functions. Preliminary results in this thesis showed that intracellular LILRA3 exists in multiple quaternary forms but is primarily secreted as monomeric protein and surprisingly is abundantly present in the nucleus of primary monocytes. Various quaternary structures of LILRA3 may contribute to its diverse biological functions. Importantly, this thesis unitised a new approach to study the quaternary structure of LILRA3 spatiotemporally at a single cell level. 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). 15/08/2016 …………………………………… …………………………………….. ……….………………… Signature Witness Signature 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: COPYRIGHT STATEMENT ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or 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 proprietary 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 Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.' Signed ……………………………………………........................... Date …15/08/2016…………………………………………........................... AUTHENTICITY STATEMENT ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format.’ Signed ……………………………………………........................... Date ……15/08/2016………………………………………........................... 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 ………………15/08/2016…………………………….............. TABLE OF CONTENT Table of contents ............................................................................................................. i List of tables ................................................................................................................... vi List of figures ................................................................................................................. vii Abbreviations .................................................................................................................. x Acknowledgments ........................................................................................................ xiv Published work from this thesis ................................................................................... xv Abstract ....................................................................................................................... xvii Chapter 1: Introduction ............................................................................................... 1 1.1 Overview ............................................................................................................ 1 1.2 Leukocyte immunoglobulin-like receptors (LILRs) .......................................... 2 1.2.1 Nomenclature of LILRs .............................................................................. 2 1.2.2 Extracellular structures of LILRs ................................................................ 3 1.2.3 Intracellular structures of LILRs ................................................................. 6 1.2.4 LILR-mediated activating or inhibitory signal transduction ....................... 8 1.2.5 Expression and regulation of LILR mRNA and/or protein ....................... 11 1.2.6 LILR ligands ............................................................................................. 13 1.2.7 In vitro functions of LILRs ....................................................................... 18 1.2.8 Genetic diversity of LILRs and their associated diseases ......................... 21 1.2.9 The expression of LILR protein in diseases .............................................. 27 1.3 Rodent orthologues of LILRs: Paired immunoglobulin-like receptors (PIRs) 29 1.3.1 The structure of PIRB ............................................................................... 30 1.3.2 PIRB ligands ............................................................................................. 30 1.3.3 In vitro and in vivo functions of PIRB ...................................................... 31 1.4 Nogo ................................................................................................................. 36 1.4.1 Nogo-A ...................................................................................................... 38 1.4.2 Nogo-B ...................................................................................................... 45 1.4.3 Nogo-C .....................................................................................................
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