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An Investigation of ADAM-Like Decysin 1 in Macrophage-Mediated Inflammation and Crohn’S Disease

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An Investigation of ADAM-Like Decysin 1 in Macrophage-Mediated Inflammation and Crohn’S Disease An Investigation of ADAM-like Decysin 1 in Macrophage-mediated Inflammation and Crohn’s Disease By Nuala Roisin O’Shea A thesis submitted to UCL for the degree of Doctor of Philosophy Division of Medicine Declaration I, Nuala Roisin O’Shea, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract Crohn’s disease (CD) is now recognised as a defective host response to bacteria in genetically susceptible individuals. The role of innate immunity and impaired bacterial clearance are widely accepted. In this thesis the role of ADAM-like, Decysin-1 (ADAMDEC1) in macrophage-mediated inflammation and gut mucosal immunity is explored. Using transcriptomic analysis of monocyte derived macrophages (MDM) ADAMDEC1 was identified as grossly under expressed in a subset of patients with CD. ADAMDEC1 was found to be highly selective to the intestine, peripheral blood monocyte-derived and lamina propria macrophages. It was shown to be an inflammatory response gene, upregulated in response to bacterial antigens and inflammation. ADAMDEC1 was expressed in prenatal and germ free mice, demonstrating exposure to a bacterial antigen is not a prerequisite for expression. Adamdec1 knock out mice were used to investigate the role of ADAMDEC1 in vivo. Adamdec1-/- mice displayed an increased susceptibility to dextran sodium sulphate (DSS), Citrobacter rodentium and Salmonella typhimurium induced colitis. In Adamdec1-/- mice, bacterial translocation and systemic infection were increased in bacterial models of colitis. These results suggest that individuals with grossly attenuated expression of ADAMDEC1 may be at an increased risk of developing intestinal inflammation as a consequence of an impaired ability to handle enteric bacterial pathogens. 3 Table of Contents Declaration .......................................................................................................................... 2 Abstract ............................................................................................................................... 3 Table of Contents ................................................................................................................ 4 List of Figures ................................................................................................................... 12 List of Tables ..................................................................................................................... 15 Acknowledgements .......................................................................................................... 16 Statement of Collaborative Work ..................................................................................... 17 List of Abbreviations ........................................................................................................ 18 1. Introduction ................................................................................................................ 23 1.1 The Intestinal Barrier and Gut Homeostasis ..................................................... 23 1.1.1 The Intestinal Microflora ................................................................................. 23 1.1.2 The Intestinal Mucosal Barrier ....................................................................... 23 1.1.3 Acute Inflammatory Response to Breach in Intestinal Barrier ......................... 28 1.1.4 Malfunction of Intestinal Barrier and Innate Immune Response to Luminal Contents ...................................................................................................................... 31 1.2 IBD ....................................................................................................................... 31 1.2.1 Epidemiology ................................................................................................. 31 1.2.2 Clinical and Histological Presentation ............................................................ 32 1.2.3 Risk factors for IBD ........................................................................................ 33 1.2.4 Current Treatment Options in IBD .................................................................. 34 1.3 Pathogenesis of CD ............................................................................................ 35 4 1.3.1 Causal Infectious Pathogens in CD ................................................................ 36 1.3.2 Role of Faecal Stream in CD ......................................................................... 36 1.3.3 Dysbiosis ....................................................................................................... 37 1.3.4 Alterations in Mucus Layer ............................................................................. 39 1.3.5 Increased Intestinal Permeability ................................................................... 39 1.3.6 Bile Salt Composition ..................................................................................... 40 1.3.7 Defective Adaptive Immunity .......................................................................... 40 1.3.8 GWAS: Candidate Genes .............................................................................. 41 1.3.9 Defective Innate Immune Response .............................................................. 44 1.3.10 Three Stage Hypothesis of CD ...................................................................... 45 1.3.11 Potential candidate molecules responsible for the defective macrophage response in CD ............................................................................................................ 46 1.4 ADAMDEC1: Published literature ...................................................................... 46 1.5 Outline of Thesis ................................................................................................. 49 2. Materials and Methods .............................................................................................. 51 2.1 Patients and Healthy Controls ........................................................................... 51 2.1.1 Subject recruitment and selection .................................................................. 51 2.1.2 Consent and sample collection ...................................................................... 52 2.1.3 Patient database ............................................................................................ 53 2.2 Adamdec1-/- and Adamdec1+/+ Mice ................................................................... 53 2.2.1 Mice Genotyping ............................................................................................ 54 2.2.2 Other Mice Strains ......................................................................................... 55 2.2.3 Mice Husbandry ............................................................................................. 55 5 2.3 Cell Isolation, Culture and Stimulation Assays ................................................ 56 2.3.1 Human Peripheral Blood MDM ...................................................................... 56 2.3.2 THP1 Cell Culture and Stimulation ................................................................. 57 2.3.3 Murine Large Bowel LP Cell Isolation ............................................................ 57 2.3.4 Murine Bone-Marrow Cells ............................................................................. 58 2.3.5 Murine Peritoneal Cavity Cells ....................................................................... 58 2.4 Antibodies ........................................................................................................... 58 2.4.1 Human Antibodies ......................................................................................... 58 2.4.2 Mouse Antibodies .......................................................................................... 59 2.5 Inhibitors of Vesicle Trafficking and Protein Degradation ............................... 59 2.6 Microarray Expression Studies .......................................................................... 60 2.7 Quantitative Reverse Transcription PCR (qRT-PCR) ....................................... 60 2.8 Sequencing of ADAMDEC1 Region ................................................................... 61 2.9 Immunoblot ......................................................................................................... 62 2.10 Histology and Immunohistochemistry .............................................................. 63 2.10.1 Histology of Human Intestine ......................................................................... 63 2.10.2 Histology of Mouse Intestine .......................................................................... 63 2.11 In Situ Hybridisation ........................................................................................... 64 2.12 Subcellular Fractionation ................................................................................... 65 2.13 Flow Cytometry ................................................................................................... 65 2.14 Cytokine Assays ................................................................................................. 66 2.15 Mouse Colitis Models ......................................................................................... 66 2.15.1 DSS Colitis ...................................................................................................
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