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Table of Contents Expression of Semaphorin 3E in Asthma and its Role in Allergic Airway Disease By Hesam Movassagh A Thesis submitted to the Faculty of Graduate Studies of The University of Manitoba in partial fulfillment of the requirements of the degree of Doctor of Philosophy Department of Immunology University of Manitoba Winnipeg, Manitoba, Canada Copyright © 2015 by Hesam Movassagh THESIS ABSTRACT Asthma is a chronic condition characterized by variable airflow obstruction, bronchial hyper- responsiveness, airway inflammation and remodeling. In spite of tremendous advances, the regulatory mechanisms controlling these pathological features have not yet been completely addressed. From an immunological perspective, type 2 inflammation and eosinophilic infiltration are the most striking hallmarks of asthma. At physiological level, structural changes such as increase in smooth muscle mass take the center stage which is usually associated with clinical measures of asthma. There might be some regulatory mediators capable of tuning airway inflammation and remodeling under homeostatic conditions but abrogated in asthmatic conditions. Semaphorin 3E (Sema3E) is an axon guidance molecule that is ubiquitously expressed and plays diverse roles in structural and inflammatory cells such as regulation of cell migration, proliferation and angiogenesis. However, its role in clinical and experimental asthma remains unclear. In this thesis, I have set out to uncover the expression and function of Sema3E in allergic asthma. It is geenrally hypothesized that Sema3E is down-regulated in allergic asthma which orchestrates the function of inflammatory (dendritic cells and neutrophils) and structural (airway smooth muscle) cells. Replenishment of Sema3E, which is suppressed under asthmatic conditions, could confer protection against allergic asthma by modulation of cellular functions. I began by comparing the expression of Sema3E between allergic asthmatics and healthy subjects. A remarkable down-regulation of Sema3E under asthmatic patients was observed which was further confirmed in a mouse model of the disease. Decreased expression of Sema3E I was specifically demonstrated on bronchial epithelial cells obtained from asthmatic patients at both mRNA and protein levels. To address the function of Sema3E in allergic asthma in vivo, I extended my studies to mouse models of the disease and demonstrated that Sema3e gene deletion results in exacerbated allergic asthma pathology induced by allergen exposure. To investigate the translational relevance of my findings, I performed treatment of an asthmatic mouse model with exogenous Sema3E in which its intranasal administration attenuated airway inflammation, remodeling and hyper- responsiveness. The mechanism underlying Sema3E’s role in pathogenesis of allergic asthma was extensively studied indicating a crucial role of this mediator in modulation of dendritic cells and neutrophils functions. Our data demonstrated that both dendritic cells and neutrophils express the Sema3E high affinity receptor, PlexinD1, which makes them responsive to Sema3E treatment. Then, I studied expression and function of PlexinD1 on human airway smooth muscle (ASM) cells. I found that PlexinD1 surface expression was reduced on ASM cells from asthmatic patients. Treatment of ASM cells with Sema3E inhibited their proliferation and migration as the characteristic feature of airway remodeling. Suppression of Rac1 GTPase activity and phosphorylation of Akt/PI3K and ERK/MAPK were found as signaling mechanisms underlying Sema3E’s inhibitory effects. Together, these findings show that Sema3E thereby appears as a novel regulatory mediator, upstream of pro-allergic events, suggestive of a new approach to attenuate allergic asthma deficits. II ACKNOWLEDGEMENTS I would like to express my sincere gratitude towards my supervisor, Dr. Abdelilah Soussi- Gounni, for his continuous support and academic guidance whilst giving me the opportunity to acquire independence in my work. I am also grateful of my research advisory committee members Drs. Aaron Marshall, Soheila Karimi and Spencer Gibson for the support and critical review of my thesis and in my research committee meetings. I am highly indebted to my external thesis examiner Dr. Jim martin, McGill University, for his insightful comments and critiques. I am also grateful for the financial support from the Manitoba Health Research Council (MHRC)/Research as well as Manitoba and Children’s Hospital Research Institute of Manitoba (CHRIM) for which this work could not have been realized. Sincere thanks are due to our collaborator Drs. Jamila Chakir from Laval University, Jonathan Duke-Cohan from Dana Farber Cancer Institute-Harvard Medical School, Jonathan McConville from University of Chicago, Dr. Michael Roth from University Hospital Basel, Fanny Mann from Aix-Marseille Université, Francis Lin and Andrew Halayko from University of Manitoba. Tremendous help from personnel at the Center for animal care services (CACS) University of Manitoba during my in vivo experiments is highly appreciated. I would like to thank all principal investigators and trainees at the Department of Immunology and also administrative support provided by Karen Morrow and Susan Ness. Last but not least, I also wish to thank my past and present labmates, especially Mrs. Lianyu Shan, not only for the technical assistance but also for the friendly atmosphere, insightful discussions and collaborations. III DEDICATIONS I dedicate this thesis with a special feeling of gratitude to my wife, Forough Khadem, who never left my side during the hard times of my studies. And it is also dedicated to all researchers who spend their life to make the world a better place to live through science! IV TABLE OF CONTENTS THESIS ABSTRACT ................................................................................................................... I ACKNOWLEDGEMENTS ......................................................................................................... III DEDICATIONS ....................................................................................................................... IV TABLE OF CONTENTS ............................................................................................................. V LIST OF TABLES ...................................................................................................................... X LIST OF FIGURES ................................................................................................................... XI LIST OF ABBREVIATIONS ..................................................................................................... XIII LIST OF COPYRIGHTED MATERIAL FOR WHICH PERMISSION WAS OBTAINED ..................... XVIII 1 CHAPTER 1: INTRODUCTION ........................................................................................... 1 1.1 Clinical overview of asthma .......................................................................................................................... 1 1.2 Asthma phenotypes ...................................................................................................................................... 2 1.3 Allergic airway inflammation ........................................................................................................................ 4 1.4 Eosinophilic vs. neutrophilic allergic asthma................................................................................................. 7 1.5 Dendritic cells ............................................................................................................................................... 9 1.6 Cytokine network in allergic asthma ........................................................................................................... 17 1.7 Airway remodeling ..................................................................................................................................... 21 1.8 Airway smooth muscle ............................................................................................................................... 25 1.9 Airway hyperresponsiveness ...................................................................................................................... 30 1.10 Semaphorins .......................................................................................................................................... 32 1.10.1 General overview of semaphorin family: History, classification, structure ......................................... 32 1.10.2 Semaphorin receptors and co-receptors ............................................................................................. 33 1.10.3 Semaphorin functions .......................................................................................................................... 36 1.10.4 Semaphorin downstream signaling ..................................................................................................... 37 1.10.5 Semaphorins in airway development, homeostasis and disease ........................................................ 38 V 1.11 Semaphorin 3E ....................................................................................................................................... 44 1.11.1 General overview ................................................................................................................................. 44 1.11.2 The phenotype of Sema3E knockout mouse ......................................................................................
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