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Reprogramming of Myeloid Compartments Supporting Tissue Repair During Dss-Induced Colitis Recovery

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Reprogramming of Myeloid Compartments Supporting Tissue Repair During Dss-Induced Colitis Recovery Georgia State University ScholarWorks @ Georgia State University Biology Dissertations Department of Biology 1-6-2017 Reprogramming of Myeloid Compartments Supporting Tissue Repair During Dss-Induced Colitis Recovery Alexandra Tremblay Follow this and additional works at: https://scholarworks.gsu.edu/biology_diss Recommended Citation Tremblay, Alexandra, "Reprogramming of Myeloid Compartments Supporting Tissue Repair During Dss- Induced Colitis Recovery." Dissertation, Georgia State University, 2017. https://scholarworks.gsu.edu/biology_diss/174 This Dissertation is brought to you for free and open access by the Department of Biology at ScholarWorks @ Georgia State University. It has been accepted for inclusion in Biology Dissertations by an authorized administrator of ScholarWorks @ Georgia State University. For more information, please contact [email protected]. REPROGRAMMING OF MYELOID COMPARTMENTS SUPPORTING TISSUE REPAIR DURING DSS-INDUCED COLITIS RECOVERY by ALEXANDRA V. TREMBLAY Under the Direction of Yuan Liu MD, PhD ABSTRACT Myeloid-derived suppressor cells (MDSC), emerging during tumor growth or chronic inflammation play a critical role in regulating T cell function. However, mechanisms governing the generation of these cells remain unclear, and need to be further defined. Using a DSS- induced colitis and recovery model, we characterized the dynamic changes within myeloid compartments and the emergence of MDSC during active and resolution phases of inflammation. We show that the immature myeloid compartment expands in bone marrow (BM) specifically at the resolution phase of inflammation during colitis transition to recovery. Additionally, we found enhanced levels of IL-17 in the serum of colitis mice tightly correlates with expansion of the IMC compartment, and is likely the factor responsible for expansion of these cells. Our study also determined that the expanded population of myeloid cells underwent a functional reprogramming event. In particular, two major functional changes occurred when colitic mice were allowed to recover: 1) CD11b+Gr-1+ myeloid cells in bone marrow and spleen acquired T cell suppressive functions, and 2) acquired the ability to enter into circulation from BM, confirming previously reported characteristics of MDSC. Additionally, we determined that acquired migratory capability in the low density myeloid cells isolated from resolution time points was due to enhanced surface expression of chemokine receptor CXCR2. Furthermore, we determined that after mobilization of MDSC from the bone marrow, these cells collected in the T cell-rich spleens, where they effectively functioned to suppress T cell proliferation. Through these acquired functions, our study determines a protective role for MDSC during the recovery phase of post-acute inflammation during persistent DSS-induced colitis. INDEX WORDS: MDSC, Colitis, IBD, Inflammation, Tissue Repair, Immunosuppression REPROGRAMMING OF MYELOID COMPARTMENTS SUPPORTING TISSUE REPAIR DURING DSS-INDUCED COLITIS RECOVERY by ALEXANDRA V. TREMBLAY A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the College of Arts and Sciences Georgia State University 2016 Copyright by Alexandra Véronique Tremblay 2016 REPROGRAMMING OF MYELOID COMPARTMENTS SUPPORTING TISSUE REPAIR DURING DSS-INDUCED COLITIS RECOVERY by ALEXANDRA V. TREMBLAY Committee Chair: Yuan Liu Committee: Deborah J. Baro Didier Merlin Electronic Version Approved: Office of Graduate Studies College of Arts and Sciences Georgia State University December 2016 DEDICATION This work is dedicated to my incredible family, both by blood and by choice. Mom, Dad, Mare, Kyle, and Jon there is no way I could have accomplished this feat without your constant love and support. I appreciate all of your patience and encouragement, and for believing in me even when I didn’t believe in myself. Thank you for always teaching me to reach for the stars. I love you all; this work is dedicated to you. iv ACKNOWLEDGEMENTS I would like to express my deepest gratitude to my mentor Dr. Yuan Liu. Your unwavering belief in my ability to succeed is the reason I have accomplished this ambitious goal. Thank you for encouraging me to trust myself, and for constantly inspiring me to strive for excellence. Thank you for never being “just a PI.” Without a doubt, you are the truest definition of a mentor. You are kind, patient, and have always looked out for my best interest above your own. You inspire me to grow as an individual, and to be confident and self-assured. Thank you for genuinely caring about not only me as PhD student, but also me as a person. Words cannot express how grateful I am to call you my mentor. I would also like to thank my committee members, Drs. Deborah Baro and Didier Merlin for their valuable insight and guidance during my graduate career. Thank you for all the enthusiasm, words of encouragement, and constructive criticism for my project. I appreciate all the hard work and patience you gave me during my graduate career. Thank you both for always supporting me, and helping me achieve my goals, it is truly appreciated. I would also like to express my gratitude to the Molecular Basis of Disease Fellowship program for providing financial support for my research for the past several years, and giving me many opportunities to present my research at GSU and at national AAI Immunology meetings. Thank you to my very large extended GSU family for your incredible scientific and emotional support. Ladies, you know who you are, thank you for knowing when to lend an ear, or a comforting shoulder to cry on, and when to give me tough love. It was such an honor to v work next to you brave, inspiring, talented, gorgeous women. I look up to each of you, and appreciate each of your unique personalities. Thanks especially to Dr. Yin-Yin Wang for helping me “tame the beast,” AKA reading many drafts of my dissertation, and providing much constructive criticism. Thank you to my lab members for helping me through all of my experiments, and for accepting me into our crazy lab family. You all are the hardest working people I have ever met, and I sincerely appreciate all of your help. vi TABLE OF CONTENTS ACKNOWLEDGEMENTS ............................................................................................. v LIST OF TABLES ........................................................................................................... xi LIST OF FIGURES ........................................................................................................ xii LIST OF ABBREVIATIONS ....................................................................................... xiv 1 INTRODUCTION ...................................................................................................... 1 1.1 The Inflammatory Response ............................................................................... 1 1.2 Initiation of Inflammation, Cytokine Signaling, and Immune Cell Recruitment 2 1.2.1 Early Inflammatory Response ........................................................................ 3 1.3 Mechanisms of Pathogen Elimination ................................................................ 6 1.3.1 Oxidative Stress ............................................................................................... 6 1.3.2 Microbiocidal Agents & PMN Degranulation .............................................. 7 1.4 Removal of Target Cells Via Phagocytosis ...................................................... 11 1.4.1 Phagocytosis .................................................................................................. 11 1.5 Progression to the Adaptive Immune Response .............................................. 14 1.6 Formation of the Immunological Synapse ....................................................... 16 1.7 Late Inflammatory Response and Wound Healing ......................................... 18 1.7.1 Late Inflammatory Phase ............................................................................. 18 1.7.2 Stages of Wound Healing ............................................................................. 21 vii 1.7.3 Changes in Microenvironment During Wound Healing ............................ 22 1.8 Dynamic Regulation of Hematopoiesis ............................................................. 26 1.8.1 Hematopoiesis Process ................................................................................. 26 1.8.2 Steady-State Hematopoiesis .......................................................................... 34 1.8.3 Demand-Adapted Hematopoiesis ................................................................. 35 1.9 The Importance of Cytokine Signaling in Inflammation ............................... 37 1.9.1 Coordinating the Inflammatory Response ................................................... 37 1.9.2 Orchestrating Immune Suppression ............................................................ 41 1.10 Inflammation is a “Double-Edged” Sword .................................................... 45 1.10.1 Acute vs. Chronic Inflammation ................................................................ 45 1.10.2 IL-17 Drives Chronic Inflammation .......................................................... 49 1.10.3 Chronic Inflammation Increases Cancer Risk .......................................... 50 1.11 Inflammatory Bowel Disease ........................................................................... 53 1.11.1 IBD: UC and CD .......................................................................................
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