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An Investigation Into Sex-Differences in the Regulation and Function of Toll-Like Receptors in Leukocyte Trafficking in Vivo

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An Investigation Into Sex-Differences in the Regulation and Function of Toll-Like Receptors in Leukocyte Trafficking in Vivo An investigation into sex-differences in the regulation and function of Toll-like receptors in leukocyte trafficking in vivo A thesis submitted for the degree of Doctor of Philosophy University of London By Emma Kay Centre for Microvascular Research William Harvey Research Institute Barts & The London School of Medicine and Dentistry Queen Mary University of London Charterhouse Square London EC1M 6BQ UK 1 Acknowledgements I would first and foremost like to express my utmost thanks to Dr Ramona Scotland for giving me the opportunity to carry out this PhD. I must also express my gratitude to Dr James Whiteford for agreeing to supervise me for the last 18 months, and for his support, encouragement, dedication, and optimism for the project. I must also thank Prof Sussan Nourshargh for acting as my second supervisor and allowing me to undertake this project in the Centre for Microvascular Research, and the British Heart Foundation for the funds to support this work. I wish to thank all the members of Microvascular Research, past and present, for their welcome, support, advice, comments and expertise during the past 3 years. I am also grateful to Dr Guglielmo Rosignoli for all the help during the hundreds of hours spent in the FACS room, Dr Lorena Gomez for her help with the bone marrow work, and Arif Mustafa for his time and assistance in the BSU. I express my thanks to Andrew Leese, with whom I have shared the ‘PhD rollercoaster’ with from the beginning, who has always been there to make me smile, and with whom I hope to stay friends for life. My thanks also go to the other students Chris, Michi, Krishma, Suborno, Thomas and Giulia for the laughs, encouragement, and friendship. A special thank you goes to Matt for the motivation, the listening, the patience, the positivity, the flexibility, and most of all the fun times. Most importantly, I am eternally grateful to my amazing parents for their love, support, and of course the roof over my head, not just in the last 3 years. To them I dedicate this thesis. 2 Abstract Sexual dimorphisms exist in the incidence and severity of many diseases, with females demonstrating relative protection from inflammatory conditions. The extent and mechanisms by which excessive leukocyte recruitment underlies these differences are not well established, and better understanding is essential for the development of targeted therapies. Evidence suggests that variances in pathogen-sensing Toll-like receptors (TLRs) underlie sex-differences in leukocyte recruitment. This thesis aimed to investigate sex-differences in trafficking of leukocytes in the zymosan peritonitis murine model of acute inflammation and furthermore evaluate if these differences were accompanied by changes in TLR2 or TLR4 expression. This work shows that female mice recruit fewer classical monocytes and neutrophils during zymosan induced peritonitis. It demonstrates female murine peritoneal macrophages are more numerous, whilst the peritoneal cytokine environments and zymosan-sensing receptors are similar between the sexes. Sex-differences were evident in the circulation as female mice showed reduced neutrophilia and monocytosis versus male counterparts, despite having similar mobilisation from bone marrow (BM) stores. The work further revealed that storage and trafficking of splenic leukocytes during acute inflammation is distinct between the sexes. Male mice have greater splenic stores of neutrophils, classical- and non-classical- monocytes, despite similar spleen sizes, signifying another source of potential pathogenic leukocytes. Furthermore, males but not females mobilise splenic classical monocytes in response to peritonitis. Conversely, neutrophils appear to traffic to the spleen in females, but not males, in this model. Whilst BM neutrophils from males displayed more TLR2 and TLR4 than females, no major differences under basal or inflamed conditions in TLR2 or TLR4 expression were evident on leukocyte subsets. This work demonstrates that males and females have distinct leukocyte trafficking profiles in acute inflammation, and suggests that the spleen, not the BM, plays a role in determining sex- differences in the available pool of immune cells. Such dimorphisms demonstrate the importance of considering gender in assay development, drug design and clinical trials. 3 Table of Contents Acknowledgements .................................................................................................. 2 Abstract .................................................................................................................... 3 List of figures .......................................................................................................... 10 List of tables ........................................................................................................... 13 Abbreviations ......................................................................................................... 14 Publications arising from this work ......................................................................... 18 Published abstracts ................................................................................................. 18 List of presentations ............................................................................................... 19 Statement of originality .......................................................................................... 20 Chapter 1: General Introduction ............................................................................. 21 1.1. Inflammation ...................................................................................................................... 21 1.2. Leukocytes ......................................................................................................................... 21 1.2.1. Macrophages .................................................................................................................. 21 1.2.2. Neutrophils ..................................................................................................................... 22 1.2.3. Classical monocytes ........................................................................................................ 23 1.2.4. Non-classical monocytes ................................................................................................. 24 1.2.5. Lymphocytes ................................................................................................................... 26 1.3. Inflammatory cell recruitment ........................................................................................... 26 1.3.1. Chemokines..................................................................................................................... 27 1.3.2. Neutrophil recruitment ................................................................................................... 27 1.3.3. Monocyte recruitment .................................................................................................... 29 1.3.4. Leukocyte adhesion cascade........................................................................................... 31 1.3.5. Leukocyte recruitment in disease ................................................................................... 33 1.3.5.1. Reperfusion Injury .................................................................................................... 33 1.3.5.2. Atherosclerosis ......................................................................................................... 34 1.3.5.3. Sepsis ........................................................................................................................ 34 1.4. Bone marrow leukocyte mobilisation ................................................................................ 35 1.5. Spleen leukocyte reservoir ................................................................................................ 38 4 1.6. Pattern Recognition ........................................................................................................... 40 1.6.1. Toll-like receptors ........................................................................................................... 41 1.6.1.1. Structure ................................................................................................................... 41 1.6.1.2. Signalling ................................................................................................................... 43 1.6.1.3. Expression: Immune cells, non-immune cells, vasculature, disease ........................ 43 1.7. Leukocyte TLRs and the deleterious effects of inflammation ........................................... 48 1.8. TLRs as therapeutic targets ................................................................................................ 49 1.9. Sex-differences ................................................................................................................... 51 1.9.1. Disease ............................................................................................................................ 51 1.9.2. Sex-differences in the inflammatory response ............................................................... 52 1.9.3. Sex hormones ................................................................................................................. 54 1.9.4. Anti-inflammatory treatment ......................................................................................... 56 1.10. Aims ................................................................................................................................
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