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The Role of Purinergic Signalling in Inflammatory Disorders University of Wollongong Research Online University of Wollongong Thesis Collection 2017+ University of Wollongong Thesis Collections 2019 The Role of Purinergic Signalling in Inflammatory Disorders Nicholas John Geraghty University of Wollongong Follow this and additional works at: https://ro.uow.edu.au/theses1 University of Wollongong Copyright Warning You may print or download ONE copy of this document for the purpose of your own research or study. The University does not authorise you to copy, communicate or otherwise make available electronically to any other person any copyright material contained on this site. You are reminded of the following: This work is copyright. Apart from any use permitted under the Copyright Act 1968, no part of this work may be reproduced by any process, nor may any other exclusive right be exercised, without the permission of the author. Copyright owners are entitled to take legal action against persons who infringe their copyright. A reproduction of material that is protected by copyright may be a copyright infringement. A court may impose penalties and award damages in relation to offences and infringements relating to copyright material. Higher penalties may apply, and higher damages may be awarded, for offences and infringements involving the conversion of material into digital or electronic form. Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong. Recommended Citation Geraghty, Nicholas John, The Role of Purinergic Signalling in Inflammatory Disorders, Doctor of Philosophy thesis, School of Chemistry and Molecular Bioscience, University of Wollongong, 2019. https://ro.uow.edu.au/theses1/571 Research Online is the open access institutional repository for the University of Wollongong. For further information contact the UOW Library: [email protected] Faculty of Science, Medicine and Health School of Biological Sciences The Role of Purinergic Signalling in Inflammatory Disorders Nicholas John Geraghty B. Med. Biotech. (Hons) This research has been conducted with the support of the Australian Government Research Training Program Scholarship A thesis submitted in (partial) fulfilment of the requirements for the award of the degree of Doctor of Philosophy Final Thesis June 2019 1 Abstract The purinergic signalling system comprises extracellular nucleotides such as adenosine triphosphate (ATP), which signals through the two P2 receptor subfamilies; P2X (P2X1-7) and P2Y (P2Y1, 2, 4, 6, 11, 12, 13, and 14). Breakdown of ATP to adenosine diphosphate (ADP) and adenosine monophosphate (AMP), by the ecto-nucleotidase ecto-nucleoside triphosphate diphosphohydrolase-1 (CD39), and finally AMP to adenosine, by ecto-5’-nucleotidase (CD73) allows activation of adenosine receptors (A1, A2A, A2B and A3). Purinergic signalling is important in inflammation and immunity, and has been implicated in transplantation, including hematopoietic stem cell transplantation (HSCT) and a major complication of allogeneic HSCT; graft-versus-host disease (GVHD). In allogeneic mouse models of GVHD, activation of P2X7, or blockade of CD73 or A2A, worsen disease, while A2A activation reduces GVHD. Purinergic signalling is also implicated in skin disorders including psoriasis. Prior to this thesis, the role of purinergic signalling in humanised models of GVHD and the imiquimod (IMQ)-induced psoriasis-like inflammatory mouse model remained unexplored. The overarching aim of this thesis was to establish a humanised non obese diabetic (NOD)- severe combined immunodeficient (SCID)-IL-2 receptor γ common chain null (IL-2Rγnull) (NSG) mouse model of GVHD in our laboratory and utilise this model to investigate the role of purinergic signalling in this disease. Additionally, this thesis aimed to establish the IMQ- induced psoriasis-like inflammatory mouse model in our laboratory and to investigate the role of P2X7 in this model. Chapter 2 details the establishment of the humanised NSG mouse model of GVHD, where NSG mice injected with human (h) peripheral blood mononuclear cells (PBMCs), subsequently develop GVHD. During this study, 10 mice developed clinical GVHD and three mice developed subclinical GVHD only. A comparison of these mice highlighted that clinical GVHD correlated with increased splenic hCD4+:hCD8+ T cell ratios, serum human interferon ii (IFN)-γ concentrations and intestinal interleukin (IL)-17 expression. Comparison of healthy mice with those with subclinical or clinical GVHD allowed characterisation of histological GVHD. This revealed leukocyte infiltration and histological damage in the liver, small intestine and skin, target organs of GVHD. Chapters 3 and 4 investigated the role of P2X7 in the humanised NSG mouse model of GVHD. A short-term regime of P2X7 blockade using Brilliant Blue G (BBG) (Chapter 3) did not impact survival, but reduced serum hIFN-γ concentrations and leukocyte infiltration and damage to the liver, small intestine and skin. A long-term regime of BBG (Chapter 4) did not impact serum hIFN-γ concentrations but reduced leukocyte infiltration and apoptosis to the livers of humanised NSG mice. Therefore, activation of P2X7 is an important signalling pathway involved in GVHD development in this model. Chapters 5 and 6 investigated the role of the CD39/CD73/A2A signalling axis in the humanised NSG mouse model of GVHD. CD39 and CD73 blockade using αβ-methylene- ADP (APCP) (Chapter 5) worsened disease through increased weight loss, leukocyte infiltration and damage to livers, and serum hIL-2 concentrations. However unlike allogeneic mouse models, adenosine receptor blockade with the broad-spectrum antagonist caffeine had no impact on disease. This suggests the accumulation of ATP rather than prevention of adenosine production is promoting GVHD. Conversely, A2A activation using CGS 21680 (Chapter 6) had differing effects on disease development. CGS 21680 caused beneficial effects through reduced leukocyte infiltration and damage in livers, and serum human tumour necrosis factor alpha (hTNF-α) concentrations. CGS 21680 also caused detrimental effects through reduced weight gain and regulatory T cell frequencies, and increased serum hIL-6 concentrations. iii Finally, Chapter 7 investigated the role of P2X7 in IMQ-induced psoriasis-like inflammation. IMQ induced ATP release from keratinocytes in vitro and up-regulated P2X7 expression in the skin of these mice. However, pharmacological blockade of P2X7 with the antagonists BBG or A804598, or P2X7 deficiency, did not impact IMQ-induced psoriasis-like inflammation. In conclusion, this thesis demonstrated for the first time that purinergic signalling pathways, predominantly the accumulation of ATP and subsequent activation of P2X7, is important in disease development in the humanised NSG mouse model of GVHD. Additionally, P2X7 is up-regulated in involved skin, but is not essential for the development of IMQ-induced psoriasis-like inflammation. iv Statement Indicating Thesis Style In accordance with the University of Wollongong “Guidelines for preparation and submission of thesis” (2017) and “Higher Degree Research (HDR) Thesis by Compilation Rules” (2017), this PhD is presented in ‘Journal Article Pre-print Compilation Style’. This thesis therefore comprises of a series of articles published in the following journals; Transplant Immunology (Chapter 2), Clinical and Experimental Immunology (Chapter 3), Cellular Immunology (Chapter 4), Immunology and Cell Biology (Chapter 5), International Immunopharmacology (Chapter 6) and Purinergic Signalling (Chapter 7). Chapters are composed of pre-print versions of the articles except for the following changes: • All language was updated to English (Australian). • Some abbreviations were altered for uniformity and clarity. • All references were updated to reflect Harvard style, and listed in one bibliography at the end of this thesis. I am the first author of all publications. I hereby declare that I was involved in the conceptualisation of these studies, I performed the experiments and data analysis except where indicated, and I prepared and authored the manuscripts. _____________________________________ Nicholas John Geraghty 2018 I consent to the presentation of the PhD in ‘Journal Article Pre-print Compilation Style’ and as Primary Supervisor I acknowledge the above statement pertaining to student contribution to be correct. _____________________________________ Associate Professor Ronald Sluyter 2018 v Publications Comprising This Thesis Published Articles Geraghty, N. J., Adhikary, S. R., Watson, D. and Sluyter, R. (2019) The A2A receptor agonist CGS 21680 has beneficial and adverse effects on disease development in a humanised mouse model of graft-versus-host disease. International Immunopharmacology, 72: 479-486. doi: 10.1016/j.intimp.2019.04.037 . Geraghty, N. J., Watson, D. and Sluyter, R. (2019) Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanised mouse model of graft-versus-host disease. Immunology and Cell Biology, Available Online 7th April, doi: 10.1111/imcb.12251 . Geraghty, N. J., Belfiore, L., Adhikary, S. R., Alexander, S. I., Sluyter, R. and Watson, D. (2019) Increased splenic human CD4+:CD8+ T cell ratios, serum human interferon-γ and intestinal human interleukin-17 are associated with clinical graft-versus-host disease in humanized mice, Transplantation Immunology, 5 4:38-46. doi: 10.1016/j.trim.2019.02.003. Geraghty, N. J., Watson,
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