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Endocannabinoid System Modulation of the Ocular Immune Response

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Endocannabinoid System Modulation of the Ocular Immune Response ENDOCANNABINOID SYSTEM MODULATION OF THE OCULAR IMMUNE RESPONSE by J. Thomas Toguri Submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Dalhousie University Halifax, Nova Scotia July 2015 © Copyright by J. Thomas Toguri, 2015 DEDICATION PAGE This thesis is dedicate this to my colleagues, friends and family, those who have been there for me through these years. ii Table of Contents List of Tables ..................................................................................................... ix List of Figures ..................................................................................................... x Abstract ............................................................................................................. xii List of Abbreviations Used ............................................................................. xiii Acknowledgments ........................................................................................... xxi Chapter I: Introduction ..................................................................................... 1 1.1 Inflammation and the Immune System .................................................... 5 1.1.1 Innate Immunity during Acute Inflammation .................................. 6 1.1.2 Immune Cells of the Innate Immune System ................................... 7 1.1.3 Adaptive Immunity during Chronic Inflammation ........................ 13 1.1.4 Cellular Recognition of Pathogens ............................................... 13 1.1.5 Vascular Dysregulation during Inflammation ............................. 14 1.2 Mechanisms of Leukocyte Recruitment during Inflammation .............. 17 1.3 The Eye and Inflammation ..................................................................... 26 1.3.1 Ocular Form and Function ........................................................... 27 1.3.2 Ocular Inflammation ..................................................................... 31 1.3.3 The Immune Privilege of the Eye: a Complicating Factor ........... 35 1.3.4 Uveitis: Intraocular Inflammation ................................................ 36 1.3.5 Etiology and Pathology of Uveitis ................................................ 37 1.3.6 Animal Models of Uveitis .............................................................. 41 1.3.7 LPS and TLR4 Signaling ............................................................... 43 1.4 The Endocannabinoid System ................................................................ 48 1.4.1 Cannabinoid Ligands for the Treatment of Ocular Inflammation .................................................................................... 48 1.4.2 Cannabinoid Receptors ................................................................. 53 iii 1.4.3 Cannabinoid Receptor Modulation for Ocular Inflammation ...... 59 1.5 Hypothesis and Objectives ..................................................................... 62 Chapter II: Methods ........................................................................................ 63 2.1 Animals .................................................................................................. 63 2.1.1 Genotyping of CB2KO mice ....................................................... 64 2.2 Anesthesia .............................................................................................. 67 2.3 Femoral Vein and Artery Catheterization of Rats ................................. 67 2.4 Endotoxemia Induced by Systemic LPS Challenge in Rats .................. 69 2.5 Endotoxin-Induced Uveitis by Intraocular Injection in Rats and Mice . 72 2.6 Intravital Microscopy ............................................................................. 73 2.7 Laser Doppler Flowmetry ...................................................................... 79 2.8 Tissue Collection ................................................................................... 80 2.9 Heamotoxylin and Eosin Staining.......................................................... 80 2.10 Multiplex Assay of Inflammatory Mediators ............................ 81 2.11 Quantitative Reverse Transcription Polymerase Chain Reaction ................................................................................ 83 2.12 Macrophage Depletion During EIU in Mice.............................. 84 2.13 Inhibition of JNK During EIU in Mice ...................................... 87 2.14 Cell Culture ................................................................................ 87 2.15 In-cell™ Westerns ..................................................................... 89 2.16 Statistical Analysis ..................................................................... 90 2.16.1 Statistics of Animal Experiments ............................................... 90 2.16.2 Statistics of Cell Culture Based Experiments ............................ 90 Chapter III: C2R activation reduces leukocyte adhesion and improves capillary perfusion in the iridial microvasculature during systemic inflammation .............................................................................................. 92 iv 3.1 Manuscript status and student contribution ........................................... 92 3.2 Abstract .................................................................................................. 93 3.3 Introduction ............................................................................................ 95 3.4 Methods .................................................................................................. 98 3.4.1 Animals ......................................................................................... 98 3.4.2 Endotoxemia ................................................................................. 99 3.4.3 Drugs ............................................................................................. 99 3.4.4 Intravital Microscopy .................................................................. 100 3.4.5 Hemodynamics ............................................................................ 101 3.4.6 Laser Doppler Flowmetry ........................................................... 101 3.4.7 Statistical Analysis ...................................................................... 103 3.5 Results .................................................................................................. 104 3.5.1 Leukocyte adherence ................................................................... 104 3.5.2 Leukocyte rolling ........................................................................ 107 3.5.3 Hemodynamics ............................................................................ 107 3.5.4 Iridial Microcirculation Blood Flow .......................................... 112 3.6 Discussion ............................................................................................ 115 3.6.1 Iridial Microcirculation as a Model for the Microcirculatory Dysfunction during Systemic Inflammation ......................................... 115 3.6.2 Cannabinoid Effects on Leukocyte-Endothelial Interactions ..... 116 3.6.3 Iridial Microvascular Blood Flow ............................................. .118 3.6.4 Conclusions ................................................................................. 120 Chapter IV: Anti-inflammatory effects of cannabinoid CB2R activation in endotoxin-induced uveitis .............................................................................. 122 4.1 Manuscript status and student contribution ......................................... 122 4.2 Abstract ................................................................................................ 123 4.3 Introduction .......................................................................................... 125 v 4.4 Methods ................................................................................................ 129 4.4.1 Animals .................................................................................... 129 4.4.2 Endotoxin-Induced Uveitis ....................................................... 130 4.4.3 Drugs ........................................................................................ 131 4.4.4 Intravital Microscopy ............................................................... 132 4.4.5 Measurements of Inflammatory Marker .................................. 138 4.4.6 Histology .................................................................................. 139 4.4.7 qRT-PCR .................................................................................. 139 4.4.8 Statistical Analysis ................................................................... 140 4.5 Results .................................................................................................. 141 4.5.1 Leukocyte-Endothelial Interactions in the Iridial Microcirculation ...................................................................... 141 4.5.2 Effects of Cannabinoids on Ocular Inflammatory Mediators .. 142 4.5.3 Effects of CB Receptor Ligands on mRNA for NF-κB and AP- 1 during Ocular Inflammation ........................................... 143 4.5.4 Effects of Clinically used Immunosuppressive Drugs in EIU .. 157 4.6 Discussion ............................................................................................ 164 4.6.1 Immunomodulatory Effects of CB2R Activation ....................... 167 4.6.2 Cannabinoid Modulation of Inflammatory Mediators ............. 168 4.6.3 Effects
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