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Fibrinogen Like Protein 2 (FGL2): a Novel Regulator of Macrophage M1 Polarization

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Fibrinogen Like Protein 2 (FGL2): a Novel Regulator of Macrophage M1 Polarization i Fibrinogen Like Protein 2 (FGL2): A Novel Regulator of Macrophage M1 Polarization by Kaveh Farrokhi A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Immunology University of Toronto © Copyright by Kaveh Farrokhi 2018 ii Fibrinogen Like Protein 2 (FGL2): A Novel Regulator of Macrophage M1 Polarization Kaveh Farrokhi Master of Science Department of Immunology University of Toronto 2018 Abstract . Fibrinogen-like protein 2 (FGL2) is a potent immunosuppressive molecule. The effects of FGL2 on macrophages, however, has not been studied. Peritoneal cell accumulation in fgl2-/-, fgl2+/+ and fgl2Tg mice in response to thioglycollate was measured. Significantly fewer cells were recovered from the peritoneal cavity of fgl2Tg mice compared to fgl2+/+ or fgl2-/- mice after thioglycollate injection. The difference in cell numbers was found to be due to decreased eosinophil accumulation in fgl2Tg mice. The effect of FGL2 on macrophage M1 and M2 polarization was next examined. IL-12 was significantly reduced in macrophages isolated from fgl2Tg mice. Addition of recombinant FGL2 protein to fgl2+/+ macrophages led to suppression of IL-12 production in a dose-dependent manner. Finally, Flow cytometric analysis of fgl2Tg macrophages revealed reduced expression of TLR4 as well as decreased phagocytosis. These data demonstrate that FGL2 inhibits the proinflammatory activity of macrophages and provides a rationale for developing anti-FGL2 therapies. iii Acknowledgments I would like to sincerely thank my supervisors, Dr. Gary Levy and Dr. Nazia Selzner for their support and guidance throughout this degree. They have served as excellent mentors and always gave me the support I needed. Their guidance has been greatly appreciated and I take the lessons they have taught with me throughout my life. I am also very appreciative and would also like to sincerely thank Dr. Andrzej Chruscinski for his guidance and help in interpreting experimental results, planning experiments and editing this thesis. This thesis would not have been possible without Dr. Chruscinski’s help and support. I would also like to thank my committee members Dr. Reginald Gorczynski and Dr. Tania Watts. for their constant support and help throughout this degree. I have learned a lot from these two great scientists and am very thankful to have them on my committee. Thank you, Mom, Dad and Kathy, for helping me through this degree and taking all those trips to come visit me, I couldn’t have done it without you. I would like to sincerely thank Angela Li, for the late nights, the cell counting, teaching me flow, putting up with my grumpy nature and the memories. This work could not be possible without you. You made the years fly by. Thank you to my peers, Hassan and Vanessa for being such great lab mates, friends, colleagues and pillars of support. Thank you to William and Jianhua for helping me with anything I needed to complete this project. You two are among the hardest working and kindest people I know. Thank you to Natalie, Lianne, Tharssun, Sarah and Arian from the flow facility for the help and answering my flow-based questions Thank you to (in no particular order): Justin Manuel, Dario Ferri, Conan Chua, Dr. Jongstra- Bilen, Andre Seigel. Dr. Shannon Dunn, Jennifer Ahn, Dr. Micheal Julius, Dr. Jennifer Gommerman the Canadian Liver Foundation and the Department of Immunology. iv Table of Contents Acknowledgments.......................................................................................................................... iii Table of Contents ........................................................................................................................... iv List of Abbreviations .................................................................................................................... vii List of Figures ..................................................................................................................................x Chapter 1 Introduction .....................................................................................................................1 Introduction .................................................................................................................................1 1.1 Macrophages ........................................................................................................................1 1.1.1 Macrophage origins and maintenance in tissue .......................................................1 1.1.2 Macrophages during embryonic development .........................................................2 1.1.3 The Role of the Macrophage in homeostasis ...........................................................3 1.1.4 Macrophages and the immune response ..................................................................4 1.1.5 Macrophage polarization and the M1/M2 paradigm ...............................................6 1.1.6 Macrophage phenotypic complexity and re-evaluation of the M1/M2 paradigm ..................................................................................................................7 1.1.7 Macrophage polarization in disease .........................................................................8 1.2 Fibrinogen-like protein 2 .....................................................................................................9 1.2.1 The coagulation cascade ..........................................................................................9 1.2.2 Genomic localization and protein structure of FGL2 ............................................10 1.2.3 Membrane-bound FGL2 ........................................................................................11 1.2.4 Soluble FGL2 .........................................................................................................12 1.2.5 The role of FGL2 in disease...................................................................................13 1.3 FGL2 and macrophage M1/M2 polarization .....................................................................16 1.4 Hypothesis and Objectives .................................................................................................17 Chapter 2 Materials and Methods ..................................................................................................18 Materials and Methods ..............................................................................................................18 v 2.1 Animal Care .......................................................................................................................18 2.2 Generation of fgl2-/- and fgl2Tg Mice .................................................................................18 2.3 Peritoneal Exudate Cells ....................................................................................................18 2.4 Production and Purification of Recombinant FGL2 Protein ..............................................19 2.5 Stimulation of Peritoneal Macrophages .............................................................................19 2.6 Griesse and Arginase Assay ...............................................................................................19 2.7 ELISA ................................................................................................................................20 2.8 Flow Cytometry .................................................................................................................20 2.9 Phagocytosis Assay ............................................................................................................20 2.10 Statistics .............................................................................................................................21 Chapter 3 Results ...........................................................................................................................22 Results .......................................................................................................................................22 3.1 Fewer cells are collected from the peritoneal cavity of fgl2Tg mice after injection of thioglycollate......................................................................................................................22 3.2 Macrophages from fgl2-/- and fgl2Tg mice express similar levels of iNOS and arginase to macrophages from fgl2+/+ mice. .....................................................................................26 3.3 Fgl2Tg macrophages produce significantly less IL-12 in response to stimulation .............28 3.4 Fgl2Tg macrophages express significantly lower TLR4 than fgl2+/+ or fgl2-/- macrophages ......................................................................................................................30 3.5 FGL2 protein suppresses IL-12 by macrophages in a dose-dependent manner. ...............32 3.6 FGL2 protein suppresses IL-12 by macrophages to a variety of stimuli ...........................34 3.7 FGL2 inhibits IL-12 at early and late timepoints after stimulation and with low and high doses of LPS. .............................................................................................................36 3.8 FGL2 inhibits IL-6 but not TNFα in response to LPS simulation .....................................38 3.9 Fgl2+/+, fgl2-/- and fgl2Tg macrophages express similar levels of MHCII and CD86 in response to LPS or IFNγ ....................................................................................................40
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