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The Glial Cell Line-Derived Neurotrophic Factor Family in Airway Infectious Disease

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The Glial Cell Line-Derived Neurotrophic Factor Family in Airway Infectious Disease The glial cell line-derived neurotrophic factor family in airway infectious disease A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Biology, Medicine and Health 2017 By Emma Connolly School of Biological Sciences Division of Infection, Immunity and Respiratory Medicine Contents List of Figures ..................................................................................................... 9 List of tables ...................................................................................................... 13 Abbreviations .................................................................................................... 14 Abstract ............................................................................................................. 17 Declaration ........................................................................................................ 18 Copyright Statement ......................................................................................... 18 Acknowledgement ............................................................................................ 19 Chapter 1 : Introduction .................................................................................... 20 1.0 Introduction ............................................................................................. 21 1.1 Airway host defence ................................................................................ 21 1.2 Tissue-resident lung macrophages ......................................................... 22 1.3 The function of tissue-resident lung macrophages .................................. 24 1.4 Regulation of alveolar macrophages by the airway epithelium ................ 24 1.5 The role of alveolar macrophages at homeostasis .................................. 26 1.6 The role of alveolar macrophages in host defence .................................. 27 1.7 Airway host defence to viral infection ...................................................... 28 1.7.1 Pattern recognition receptors ............................................................ 28 1.7.2 Toll-like receptors ............................................................................. 28 1.7.3 The Interferons ................................................................................. 31 1.8 Airway host defence to Influenza virus infection ...................................... 34 1.8.1 Interferon-stimulated genes important in influenza virus infection .... 35 1.8.2 Dysregulation of the type I IFN response .......................................... 36 1.9 The role of macrophages in airway disease ............................................ 36 1.9.1 The adaptation and plasticity of macrophages to their environment . 36 1.9.2 Classically activated and alternatively activated macrophages......... 37 1 1.10 Chronic airway disease ......................................................................... 38 1.11 Neuroimmune crosstalk ......................................................................... 40 1.12 Neurotrophic factors .............................................................................. 41 1.12.1 The glial cell line-derived neurotrophic factor family ....................... 42 1.12.2 RET-dependent GDNF family signalling ......................................... 43 1.12.3 GDNF family signalling in lipid rafts ................................................ 44 1.12.4 RET-independent GDNF family signalling ...................................... 45 1.12.5 The functions of the GDNF family in the nervous system ............... 45 1.12.6 The GDNF family in neurological diseases ..................................... 46 1.13 The neuroimmune crosstalk in lymphatic tissue .................................... 46 1.14 The neuroimmune crosstalk in mucosal tissue ...................................... 47 1.15 The functions of the GDNF family outside of the nervous system ......... 48 1.16 The role of the GDNF family in lymphatic tissue .................................... 49 1.17 The role of the GDNF family in the Intestine .......................................... 49 1.18 The peripheral nervous system and neurotrophic factors in chronic airway disease ............................................................................................... 50 1.19 Research hypothesis and aims ............................................................. 53 Chapter 2 : Methods ......................................................................................... 54 2.1 Mouse strains .......................................................................................... 55 2.2 Mouse experimental models .................................................................... 55 2.2.1 Influenza infection model .................................................................. 55 2.2.2 House dust mite model ..................................................................... 55 2.3 Isolation of mouse tissue cells ................................................................. 56 2.3.1 Isolation of murine bone marrow cells............................................... 56 2.3.2 Culture of murine bone marrow-derived macrophages ..................... 56 2.3.3 Isolation of mouse bronchoalveolar lavage macrophages ................ 56 2.3.4 Digestion of mouse lung tissue ......................................................... 57 2 2.3.5 Digestion of mouse ear and back skin tissue .................................... 57 2.4 Isolation of human tissue cells ................................................................ 58 2.4.1 Isolation of human peripheral blood monocytes................................ 58 2.4.2 Culture of human monocyte-derived macrophages .......................... 58 2.4.3 Isolation of human bronchoalveolar lavage macrophages ................ 59 2.4.4 Isolation and culture of airway macrophages from human lung resection samples ...................................................................................... 59 2.4.5 Sputum sample collection and processing ........................................ 60 2.5 Cell line culture ........................................................................................ 60 2.5.1 Beas-2b cells .................................................................................... 60 2.5.2 A549 cells ......................................................................................... 61 2.5.3 THP-1 cells ....................................................................................... 61 2.6 mRNA detection assays .......................................................................... 61 2.6.1 RT-qPCR .......................................................................................... 61 2.6.2 RT2 Profiler PCR array for mouse neurotrophins and receptors ....... 62 2.7 Protein detection assays ......................................................................... 63 2.7.1 Concentrating protein in supernatants .............................................. 63 2.7.2 Cytokine Bead Array ......................................................................... 63 2.7.3 Human TNFα and IL-6 ELISAs ......................................................... 64 2.7.4 Human and mouse Neurturin ELISAs ............................................... 64 2.7.5 Western Blotting ............................................................................... 65 2.7.6 Immunocytochemistry and immunofluorescence .............................. 65 2.7.7 PathScan Antibody Array Kits (Fluorescent Readout) ...................... 66 2.7.8 Flow cytometry .................................................................................. 66 2.8 Phagocytosis assay ................................................................................. 70 2.9 Cell death detection assays .................................................................... 70 3 2.9.1 Annexin V flow staining ..................................................................... 70 2.9.2 LDH assay ........................................................................................ 70 2.10 Statistics ................................................................................................ 71 Chapter 3 : Characterisation of the GDNF family receptor, GFRα2, on airway macrophages in health and disease ................................................................. 72 3.1 Introduction .............................................................................................. 73 3.1.1 Neuronal factor function outside the nervous system ....................... 73 3.1.2 Are neuronal factors expressed on airway immune cells? ................ 73 3.1.3 The GDNF family expression and signalling on airway cells ............. 74 3.1.4 The role of the GDNF family in disease ............................................ 75 3.1.5 Hypothesis ........................................................................................ 76 3.1.6 Aims .................................................................................................. 76 3.2 Results .................................................................................................... 77 3.2.1 Screening mouse macrophages for neurotrophic factors.................. 77 3.2.2 The expression of the GDNF family on mouse bone marrow-derived macrophages ............................................................................................. 82 3.2.3 The cytokine IL-4 enhances the mRNA of the GFRα2 receptor
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