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The Immunomodulatory Effects of Nociceptin – Development and Validation of a Biosensor Assay

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The Immunomodulatory Effects of Nociceptin – Development and Validation of a Biosensor Assay THE IMMUNOMODULATORY EFFECTS OF NOCICEPTIN – DEVELOPMENT AND VALIDATION OF A BIOSENSOR ASSAY Thesis submitted for the degree of Doctor of Philosophy at the University of Leicester by Christopher Paul Hebbes MBChB BSc MMedSci FRCA FFICM Department of Cardiovascular Sciences February 2021 Supervisors Professor Jonathan P. Thompson Professor David G. Lambert I. Abstract The immunomodulatory effects of nociceptin – development and validation of a biosensor assay Christopher Hebbes Opioids have long been associated with increased susceptibility to infectious diseases, and the role of the classical opioids in immunomodulation is a subject of some debate. A fourth opioid-like receptor, sharing significant sequence homology, and Gi mechanism, to the classical MOP, DOP and KOP opioid receptors has emerging evidence for its expression throughout the immune system. Furthermore, observational evidence suggests that the concentration of nociceptin, the endogenous agonist for this receptor increases in the human plasma, synovial fluid and sputum sampled in the context of inflammatory conditions. Administration of exogenous nociceptin worsens mortality in an animal model of sepsis, further suggestive that this non-classical opioid may have an immunomodulatory role in-vivo. Despite limited observational evidence, localising the source of the increased nociceptin concentration has been challenging, because of its low concentration and problems with existing use of ELISA and RIA tests. Chimeric G-proteins facilitate non-classical coupling between intracellular pathways, allowing the use of new markers as a readout of receptor activation, and therefore local detection of agonist ligands and their concentration. This work validated the design of a chimeric G-protein based biosensor test to detect nociceptin release from a single cell. In principle, the biosensor facilitated nociceptin receptor coupling via Gq to calcium flux for a non-invasive and non-radioactive readout of receptor activation. The validated test was used to investigate nociceptin release from immunocytes (and subtypes) from healthy individuals and patients admitted to the intensive care unit with sepsis. These data were correlated with additional PCR and immunohistochemistry tests to determine expression of nociceptin, its receptor and their precursors. In general, mixed granulocytes were found to release nociceptin. In evaluating immunocyte subsets, both nociceptin and its receptor are found in eosinophils and neutrophils from individuals with sepsis, and when incubated in an environment mimicking sepsis, suggesting upregulation of this system in sepsis. i II. Acknowledgements Science is built on the hard work of others in a quest for new knowledge, and this work is no exception. Firstly, I thank my supervisors Jonathan Thompson and Dave Lambert for their patience, thoughtful critique and encouragement. Much of the groundwork for this project was undertaken by Simon Scott and Mark Bird, to whom I am indebted. As a physician-scientist, the combination of two disciplines has been challenging – and I thank my clinical and basic science colleagues for their support in this endeavour. Notably, I am indebted to the lab team, John, Mark, Laki, Barbara and Jonathan for their careful instruction, advice, and comments, to Jenny for her flow cytometry expertise, and to Clett for his NovoStar tuition. As a firm believer in open source, I am grateful to colleagues at the data science breakfast club and the #rstats community for introducing me to the world of R. To this end, much of this project is built upon open source software, Python, R, Inkscape, FCSAlyzer. The work from this project is, in part funded by a BBSRC grant, and the clinical study was supported by the Royal College of Anaesthetists Ernest Leech fund. The use of the confocal microscope was supported by the Advanced Imaging Facility at the University of Leicester. No man is an island, however much he might wish to be. A heartfelt thanks to my parents, and my partner Benjamin for his love and support – and finally to our dog, Oscar, for reminding me when to stop writing and go for a walk. ii III. Contents I. Abstract ............................................................................................................. i II. Acknowledgements ........................................................................................... ii III. Contents ....................................................................................................... iii IV. Abbreviations ............................................................................................. viii V. List of tables ................................................................................................... xiii VI. List of figures ...............................................................................................xvi 1 Introduction ...................................................................................................... 1 1.1 General introduction .......................................................................................... 1 1.2 Pharmacology of N/OFQ .................................................................................... 1 1.2.1 Structure and localisation of N/OFQ and its receptor ................................ 1 1.2.2 Cellular mechanisms following NOP activation .......................................... 5 1.2.3 In-vivo actions of N/OFQ-NOP .................................................................... 9 1.2.4 Key points.................................................................................................. 14 1.3 The immune system in health and disease ...................................................... 15 1.3.1 Cells of the immune system ...................................................................... 18 1.3.2 Innate immunity ....................................................................................... 25 1.3.3 Inflammation and Inflammatory conditions ............................................. 25 1.3.4 Sepsis ........................................................................................................ 29 1.3.5 Key points.................................................................................................. 34 1.4 Role of N/OFQ-NOP in the immune system ..................................................... 35 1.4.1 Methods of investigating and characterising the NOP-N/OFQ system .... 36 1.4.2 In-vitro evidence for N/OFQ-NOP localisation ......................................... 46 1.4.3 Modelling inflammation ........................................................................... 53 iii 1.4.4 Possible mechanisms and targets for NOP-N/OFQ immune signalling .... 58 1.4.5 Key points.................................................................................................. 61 1.5 Aims and objectives ......................................................................................... 62 2 Materials and Methods ................................................................................... 64 2.1 Project overview .............................................................................................. 64 2.2 Cell Culture ....................................................................................................... 68 2.2.1 Protocol 1 - Maintenance of transfected immortalised cell lines ............ 68 2.2.2 Protocol 2 - Cell counting .......................................................................... 70 2.3 Fluorescence-based assays .............................................................................. 72 2.3.1 Principles of fluorescence ......................................................................... 72 2.3.2 Biological measurements using fluorophores. ......................................... 75 2.3.3 Ligands used for characterisation of cell lines and testing ....................... 82 2.3.4 Principles of confocal microscopy for live samples .................................. 84 2.4 Confocal microscopy ........................................................................................ 88 2.4.1 Protocol 3 - Preparation of glass coverslips .............................................. 88 2.4.2 Protocol 4 - Live cell confocal imaging of Calcium Flux in CHO cells ........ 88 2.4.3 Protocol 5 - Immunofluorescent staining of immune cells ...................... 92 2.5 Cuvette based fluorometry .............................................................................. 96 2.5.1 Protocol 6 - Cell preparation ..................................................................... 96 2.5.2 Protocol 7 - Fluorometric measurement of calcium concentration using Fura-2-AM dye ......................................................................................................... 97 2.5.3 Protocol 8 - Data analysis ......................................................................... 97 2.6 Extraction of Leucocytes .................................................................................. 98 2.6.1 Techniques for density gradient separation ........................................... 102 2.6.2 Techniques for isolation of immune cell populations by cell surface markers 108 iv 2.7 Characterisation of immune cells by flow cytometry .................................... 115 2.7.1 Principles of Flow Cytometry .................................................................. 115 2.7.2 Protocol 14 - Validation of immune cell separation by Flow Cytometry 118 2.8 Luciferase ATP
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