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Examining the Role of Non-Canonical NOD-Like Receptors and Inflammasomes in Inflammation and Disease University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2018-03-21 Examining the Role of Non-Canonical NOD-like Receptors and Inflammasomes in Inflammation and Disease Platnich, Jaye Matthew Platnich, J. M. (2018). Examining the Role of Non-Canonical NOD-like Receptors and Inflammasomes in Inflammation and Disease (Unpublished doctoral thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/31757 http://hdl.handle.net/1880/106465 doctoral thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY Examining the Role of Non-Canonical NOD-like Receptors and Inflammasomes in Inflammation and Disease by Jaye Matthew Platnich A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY GRADUATE PROGRAM IN IMMUNOLOGY CALGARY, ALBERTA MARCH, 2018 © Jaye Matthew Platnich 2018 Abstract The NOD-like Receptors (NLRs) are a family of pattern recognition receptors known to regulate a variety of immune signaling pathways. A substantial portion of NLR research focuses on the pyrin domain-containing NLRP subfamily. The canonical NLRPs are inflammasome-forming proteins responsible for the activation of caspase-1 and the maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18. In contrast, the non-canonical inflammasome-independent NLRPs regulate a variety of other pathways, including MAPK and NF-κB, through the formation of non-inflammasome complexes. Interestingly, not all inflammasomes are nucleated by NLRPs. The recently characterized non-canonical caspase-4 (caspase-11 in mice) inflammasome is known to be a key driver of the innate immune response to intracellular pathogens (and the molecules associated with them), by triggering both inflammatory cell death and the activation of canonical inflammasomes. At the outset of this PhD work, the understanding of both non-inflammasome- forming NLRPs and the non-canonical caspase-4 inflammasome was poor and the studies were sparse. It was the goal of this thesis to characterize the expression, gene regulation, and function of the non-inflammasome-forming NLR protein NLRP6, both at the cellular and biochemical level. Furthermore, using a pathogen-associated molecular pattern (PAMP)-driven model of inflammation, we sought to elucidate the function of the non- canonical caspase-4 inflammasome, particularly as it pertains to the regulation of the canonical inflammasome and cell death. ii By studying the fundamental biology underlying these lesser-known mediators of the innate immune system, we hoped to better understand their contribution to the early immune response and their role in driving inflammatory disease with a view to, one day, ameliorating the condition of patients suffering from these afflictions through the development of targeted therapeutics. iii Acknowledgements They say it takes a village to raise a child, and a PhD project is akin to the most squalling and unruly child imaginable. I could not have completed this work without the intellectual, technical, and emotional support of many individuals. First, I’d like to sincerely thank my supervisor, Dr. Dan Muruve. You are among the cleverest people I’ve had the pleasure to meet and you have been a constant source of inspiration to me. Your steadfast commitment to my development as a scientist has been invaluable in terms of time, effort, and financial support. I would also like to thank the other professors that served as mentors to me, namely Drs. May Ho, Justin MacDonald, and Hank Duff. Second, I’d like to extend my thanks to my current and former labmates Arthur Lau, Adom Bondzi-Simpson, Christie Sandall, Nathan Bracey, Sharon Clark, Hyunjae “JC” Chung, Kosh Vilaysane, Justin Chun, and Takanori “Tak” Komada. I’d name you all as friends, but over the past four years we truly have become family. I can’t imagine a better group to have spent my time with and I wish you all the best in your future endeavors. Third, I want to express my deepest gratitude to my family. My parents, Tim and Tracy, and my sister Casey have been my bedrock of support throughout this project and I would not have been able to complete it without you. I love you all beyond my ability to convey with words. Last, but certainly not least, I want to offer my heartfelt thanks to my friends. 2017-2018 was a very challenging year for me, both academically and personally. Many iv of you saw me at my emotional nadir and rose to the occasion magnificently. I cannot even begin to repay the kindness and patience you showed me. In particular, I would like to express my profound gratitude to Matt and Maryna Szojka, Alec Campbell, Alex Pynn, David Guzzardi, Arthur Lau, Christie Sandall, Adom Bondzi-Simpson, and Richard Magbojos for the special efforts you all made on my behalf. v Table of Contents Abstract ............................................................................................................................... ii Acknowledgements ............................................................................................................ iv Table of Contents ............................................................................................................... vi List of Tables ...................................................................................................................... x List of Illustrations and Figures ......................................................................................... xi List of Abbreviations ....................................................................................................... xiv Chapter One: Introduction .................................................................................................. 1 1.1 Introduction .................................................................................................... 2 1.2 Pattern Recognition Receptors (PRRs) and the Innate Immune System ....... 3 1.2.1 Innate Immunity and Pattern Recognition Receptors (PRRs) ........ 3 1.2.2 NOD-like Receptors (NLRs) .......................................................... 4 1.3 Canonical NLRs and Inflammasomes ........................................................... 9 1.3.1 Canonical Inflammasomes .............................................................. 9 1.3.2 NLRP1 Inflammasome ................................................................. 10 1.3.3 NLRC4 Inflammasome ................................................................. 11 1.3.4 AIM2 Inflammasome .................................................................... 12 1.3.5 Pyrin Inflammasome ..................................................................... 13 1.3.6 NLRP3 Inflammasome ................................................................. 13 1.4 Non-Inflammasome-Forming NLRs (Including Non-Canonical NLRP Proteins) and Their Functions ............................................................................... 16 1.4.1 NOD1/2 ......................................................................................... 17 1.4.2 NLRP3 .......................................................................................... 17 1.4.3 NLRP6 and NLRP12 .................................................................... 18 1.5 NLRP6 ......................................................................................................... 19 1.5.1 Structure ........................................................................................ 19 1.5.2 Expression ..................................................................................... 24 1.5.3 Function ........................................................................................ 25 1.6 Non-Canonical Inflammasome and Pyroptotic Cell Death ......................... 28 1.6.1 Non-Canonical Inflammasome ..................................................... 28 1.6.2 Pyroptosis ...................................................................................... 29 1.6.3 NLRP3 Activation by the Non-Canonical Caspase-4 Inflammasome ........................................................................................... 35 1.7 Normal Kidney Physiology and Disease States .......................................... 37 1.7.1 Kidney Physiology ........................................................................ 37 1.7.2 Pathogenesis of Kidney Disease ................................................... 37 1.8 Summary, Rationale, and Hypotheses ......................................................... 39 1.8.1 NLRP6 Project .............................................................................. 40 1.8.2 Non-Canonical Caspase-4 Inflammasome Project ....................... 41 vi 1.8.3 Contextual Importance of this Work ............................................. 42 Chapter Two: Materials and Methods ............................................................................... 43 2.1 Materials ...................................................................................................... 44 2.1.1 Reagents, Kits, and Buffers .......................................................... 44
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