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Studies on the Role of Formyl Peptide Receptors in Pituitary and Adrenal

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Studies on the Role of Formyl Peptide Receptors in Pituitary and Adrenal STUDIES ON THE ROLE OF FORMYL PEPTIDE RECEPTORS IN PITUITARY AND ADRENAL FUNCTION. By Vance Alexander Naughton A thesis submitted to Imperial College London for the degree of Doctor of Philosophy. Section of Investigative Medicine Department of Medicine Imperial College London 1 Declaration of Copyright The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work. 2 Declaration of Originality I hereby declare that all work submitted within this thesis is my own, and where I have received help or collaborated, I have referenced and acknowledged this accordingly. 3 Acknowledgements Those acknowledged are (were) based at Imperial College London unless stated otherwise. The Fpr2/3 knockout mice were generated as part of a collaborative project between Prof. Roderick Flower and Prof. Mauro Perretti (William Harvey Research Institute, London), Prof. John Morris (University of Oxford), and Prof. Julia Buckingham. Many thanks to Dr. Bradley Spencer-Dene (London Research Institute) for guidance during the immunohistochemistry experiments. Thank you to Paul Nya and colleagues for their tissue processing service (Histopathology, Hammersmith Hospital, London). I am grateful to Djordje Gveric (UK Multiple Sclerosis Tissue Bank) for help in obtaining human pituitary glands. Thank you to Dr. Federico Roncaroli, for his expert interpretation of slides from the human pituitary immunohistochemistry study. Thank you to Prof. Mohammed Ghatei, Dr. Michael Patterson, and Dr. Chris John for peptide iodinations. I am thankful to Prof. Dominic Wells and Prof. David Nutt for their useful insights. Finally, I thank my supervisors Dr. Chris John and Prof. Julia Buckingham for their support throughout this project. 4 Abstract The mechanism by which glucocorticoids (GCs) achieve negative feedback on the release of hypothalamo-pituitary-adrenal (HPA) axis hormones has long been under investigation. Annexin A1 (ANXA1) is a key mediator of the effects of GCs within the neuroendocrine and immune systems. Previous research suggested the negative feedback effect of the GC-ANXA1 system on the pituitary release of adrenocorticotrophic hormone (ACTH) was mediated via a member of the formyl peptide receptor (Fpr in rodents, FPR in humans) family. The present work tested the hypothesis that specific Fpr/FPR subtypes modulate both pituitary and adrenal function in terms of stress hormone (ACTH and corticosterone) secretion (following exposure to secretagogues CRH and ACTH or the inflammogen LPS in rats), and their tissue distribution (mice and rats) will itself be upregulated following inflammogenic stress (LPS in mice and rats, multiple sclerosis in human tissue). This was achieved through 1) immunohistochemical detection of FPR1, FPR2/ALX, and FPR3 in human anterior pituitary sections, and of green fluorescent protein (GFP) in HPA axis tissues from Fpr2/3-/-, GFP+/+ mice; 2) measurement of basal and stimulated ACTH and GC release from dispersed rat anterior pituitary and adrenal cells, incubated with agonists and antagonists for FPR1, FPR2/ALX and FPR3, namely, formyl- Met-Leu-Phe (fMLF), ANXA1 amino-acetylated peptide (ANXA1Ac2-26), Trp-Lys-Tyr-Met-Val-D-met (WKYMVm), haem-binding protein fragment (F2L), aspirin-triggered lipoxin A4 (15-epi-LXA4), and Trp-Arg-Trp-Trp-Trp-Trp (WRW4). These ligands were found to elicit a range of modulatory, concentration-dependent effects on pituitary ACTH and adrenal GC secretion. Evidence was found for the spatial distribution of: FPR3 and FPR2/ALX within the human anterior pituitary, and GFP (as a surrogate for Fpr2/3) colocalised with ACTH, growth hormone (GH), and prolactin (PRL) within the Fpr2/3-/-, GFP+/+ mouse pituitary. The findings contribute evidence in support of a role of Fpr/FPR subtypes and their ligands as modulators of pituitary and adrenal hormone release. 5 Table of Contents Chapter One: Introduction ............................................................................................................................. 17 1.1 BACKGROUND ..................................................................................................................................... 18 1.2 ANATOMY AND PHYSIOLOGY OF THE HPA AXIS ....................................................................... 21 1.2.1 Overview of the HPA axis ............................................................................................................... 21 1.2.2 Role of glucocorticoids .................................................................................................................... 23 1.2.3 Regulation of glucocorticoid release ............................................................................................... 30 1.2.4 Hypothalamic control of ACTH secretion ....................................................................................... 36 1.2.5 The stress response .......................................................................................................................... 39 1.2.6 Negative feedback control of CRH/AVP and ACTH secretion ....................................................... 43 1.3 HPA AXIS RESPONSES TO INFLAMMOGENIC STRESS ............................................................... 46 1.3.1 The HPA-immune system................................................................................................................ 46 1.3.2 Mechanisms of HPA activation during infection ............................................................................. 47 1.3.3 Evidence for inflammogen receptors within the pituitary gland ...................................................... 50 1.3.4 Evidence for inflammogen receptors within the adrenal gland ....................................................... 50 1.4 ROLE OF ANNEXIN A1 IN MODULATING HPA AXIS FUNCTION .............................................. 53 1.4.1 Basic annexin A1 biology ................................................................................................................ 53 1.4.2 Effects of ANXA1 within the HPA axis .......................................................................................... 54 1.4.3 Mechanism of action of annexin A1 within the anterior pituitary gland ......................................... 55 1.5 ANNEXIN A1 SIGNALLING AND THE ROLE OF THE FORMYL PEPTIDE RECEPTOR (FPR/FPR) FAMILY .......................................................................................................................... 59 1.5.1 Biology of the Fpr/FPR family ........................................................................................................ 59 1.5.2 Formyl peptide receptor 1 (FPR1) ................................................................................................... 61 1.5.3 Formyl peptide receptor 2/ lipoxin receptor (FPR2/ALX) .............................................................. 62 1.5.4 Formyl peptide receptor 3 (FPR3) ................................................................................................... 64 1.5.5 Translation of rodent Fpr and human FPR biology ......................................................................... 65 1.6 EFFECTS OF INFLAMMOGENS ON HPA AXIS ACTIVITY, ANXA1, AND THE FPR/FPR FAMILY ............................................................................................................................................. 68 1.6.1 The role of pituitary ANXA1 and the Fpr/FPR family in response to an inflammogen .................. 69 1.6.2 The role of adrenal ANXA1 and the Fpr/FPR family in response to an inflammogen .................... 69 1.7 HYPOTHESIS, AIMS, AND OBJECTIVES .......................................................................................... 71 6 Chapter Two: Materials and Methods ........................................................................................................... 79 2.1 OVERVIEW ............................................................................................................................................ 80 2.2 MATERIALS .......................................................................................................................................... 84 2.2.1 Drugs ............................................................................................................................................... 84 2.2.2 Human tissues .................................................................................................................................. 86 2.3 ANIMALS ............................................................................................................................................... 87 2.3.1 Fpr2 and Fpr3 knockout (Fpr2/3-/-) mice ......................................................................................... 87 2.3.2 Rats .................................................................................................................................................. 89 2.4 IN VIVO METHODS ............................................................................................................................... 91 2.4.1 Time course of responses to intraperitoneal injection of
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