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(Or Proton-Activated) Receptor - GPR4 and OGR1 in Intestinal Inflammation

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(Or Proton-Activated) Receptor - GPR4 and OGR1 in Intestinal Inflammation Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2015 Role of the pH-sensing receptor GPR4 and OGR1 in intestinal inflammation Wang, Yu Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-110560 Dissertation Published Version Originally published at: Wang, Yu. Role of the pH-sensing receptor GPR4 and OGR1 in intestinal inflammation. 2015, University of Zurich, Faculty of Science. Role of pH-sensing (or Proton-Activated) Receptor - GPR4 and OGR1 in Intestinal Inflammation Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Yu WANG (王瑜) aus China Promotionskomitee: Prof. Dr. med. Carsten A. Wagner (Vorsitz und Leitung der Dissertation) Prof. Dr. med. Dr. phil. Gerhard Rogler (Koleiter der Dissertation) Dr. rer. nat. Isabelle Frey-Wagner Dr. rer. nat. Klaus Seuwen Zürich, 2015 1 TABLE OF CONTENTS TABLE OF CONTENTS ..................................................................................................... 2 SUMMARY ..................................................................................................................... 5 ZUSAMMENFASSUNG ................................................................................................. 10 CHAPTER 1 ................................................................................................................... 15 INTRODUCTION ........................................................................................................... 15 1.1 INFLAMMATION AND IMMUNE RESPONSE ................................................................ 16 1.1.1 Introduction .............................................................................................. 16 1.1.2 Th1 and Th2 cells in the adaptive immune system ................................. 18 1.1.3 Overview of Th1, Th2, Th17 and Treg ...................................................... 21 1.2 INFLAMMATORY BOWEL DISEASE (IBD) ................................................................. 23 1.2.1 A Brief Introduction to IBD ....................................................................... 23 1.2.2 Epidemiology ............................................................................................ 23 1.2.3 Pathogenesis of IBD ................................................................................. 24 1.2.4 The intestinal mucosal immune system .................................................. 25 1.2.5 CD is a Th1/Th17 response and UC is a Th2-like response ...................... 30 1.2.6 Overview of susceptibility loci implicated in IBD by GWAS .................... 31 1.3 IBD AND ACIDIC PH ............................................................................................ 35 1.3.1 Inflammation and acidic pH .................................................................... 35 1.3.2 IBD and acidosis ....................................................................................... 38 1.4 PROTON SENSING RECEPTOR FAMILY ...................................................................... 42 1.5 MOUSE MODELS USED IN IBD STUDY ..................................................................... 48 1.6 AIM OF THE PROJECT ........................................................................................... 51 CHAPTER 2 ................................................................................................................... 52 PUBLICATIONS THAT CONTRIBUTED TO THAT WORK ................................................ 52 2 CHAPTER 3 ................................................................................................................... 55 DISCUSSION ................................................................................................................. 55 3.1 AMELIORATED COLITIS IN MICE LACKING GPR4 OR OGR1 ......................................... 56 3.2 THE PROPOSED MECHANISM OF GPR4 MEDIATED INFLAMMATION AGGRAVATION .......... 58 3.3 SEVERAL LINES OF EVIDENCE TO SUPPORT THE DESTRUCTIVE ROLE OF ACTIVATED GPR4 IN THE PROGRESSION OF INFLAMMATION ............................................................................... 59 3.4 PROGRESS IN GPR4 DOWNSTREAM SIGNALING PATHWAY STUDIES ............................... 61 3.5 PROGRESS IN DEVELOPMENT OF GPR4 INHIBITORS ................................................... 63 3.6 OGR1 AND INFLAMMATION ................................................................................. 64 3.7 GENDER DEPENDENT EFFECT OF OGR1 ................................................................... 65 3.8 OTHER PROTON SENSORS AND THE DIGESTIVE SYSTEM ............................................... 66 CHAPTER 4 ................................................................................................................... 69 FUTURE PERSPECTIVES ................................................................................................ 69 REFERENCES ................................................................................................................. 72 CURRICULUM VITAE .................................................................................................... 81 ACKNOWLEDGEMENTS ............................................................................................... 83 LIST OF ABSTRACTS ..................................................................................................... 86 3 4 Summary Inflammatory bowel disease (IBD), a common chronic inflammatory disorder of the gastrointestinal system, has been studied for decades. To clarify the pathogenesis of IBD and breakthrough the bottleneck of treatment remains a formidable task. It is widely acknowledged that inflammatory or tumor tissues exhibit elevated glucose uptake and local acidic pH due to hypoxia, excessive production and insufficient elimination of glycolytic metabolites. Recently, a novel family of proton sensing G-protein coupled receptors (GPCRs) including GPR4, ovarian cancer G protein coupled receptor 1 (OGR1, GPR68) and T-cell death associated gene 8 (TDAG8, GPR65) has been identified. All of these receptors are activated by protons in the physiological range around pH 7.4. The intraluminal gastrointestinal pH in patients with active IBD is significantly decreased. Local acidification, as low as pH 2.3, has been observed during intestinal inflammation and implicated in the pathogenesis and progression of IBD. The role of proton-activated GPCRs in the pathogenesis of inflammation is mostly unknown. The aim of the thesis project is to unravel the relationship between pH receptors and IBD and to answer the question whether GPR4 and OGR1 5 may be involved in the pathogenesis of IBD. Here, we used two animal models to test our hypothesis; the dextran sulphate sodium (DSS) induced chronic colitis model and the IL10 KO mouse model, a spontaneous colitis model. DSS was used to induce chronic colitis in GPR4 knockout mice (Gpr4 -/-, in Balb/c and C57Bl/6 background) and their respective wild-type controls (Gpr4 +/+, in Balb/c and C57Bl/6 background), to resemble ulcerative colitis (UC). Mice in both groups received 4 cycles of DSS treatment, while additional control groups of both genotypes received only normal water. In each cycle, 3% DSS was administered for 7 days in drinking water followed by 10 days of recovery with tap water. Mice were sacrificed after 5 weeks recovery after the last DSS cycle. Body weight was monitored and colon samples were collected for histology, cytokine mRNA expression, and myeloperoxidase (MPO) activity quantification. The colonoscopy score, colon length, and spleen weight were also used to assess the severity of colitis. For the spontaneous colitis model, Ogr1 -/- and Gpr4 -/- mice (C57Bl/6) were crossed into interleukin-10 knockout (IL-10 -/-) mice (C57Bl/6), a spontaneous colitis model simulating Crohn's disease (CD), to generate Gpr4 +/+ /Ogr1 -/- /IL-10 -/- or Gpr4 -/- /Ogr1 +/+ /IL-10 -/- mice. The 6 development of rectal prolapse, a marker of severe intestinal inflammation, was followed over 200 days. The incidence of rectal prolapses in double knockout mice was compared with IL-10 -/- from the same litters. Kaplan-Meier survival analysis was introduced to evaluate whether deficiency of pH receptors could change prolapse occurrence. Moreover, to eliminate the bias and influence of severe colitis and development of prolapse, another group of mice was sacrificed at age 80 days, before any of the mice developed prolapses. Severity of colitis was assessed by the conventional parameters cytokine mRNA expression, histological score, MPO activity, colon length, and spleen weight. Lamina propria leukocytes (LPLs) from large intestine in mice were freshly isolated and characterized by flow cytometry assay. After induction of chronic DSS colitis in Gpr4 +/+ and Gpr4 -/- mice, Gpr4 -/- mice showed less body weight loss (p <0.05 *) and lower histology scores (p <0.001 ***) indicating less severe inflammation. No significant difference in MPO activity and spleen weight was found. In the spontaneous colitis model, Kaplan-Meier survival analysis showed a significantly delayed onset and progression of rectal prolapses in female Gpr4 +/+ /Ogr1 -/- /IL-10 -/- mice relative to female Gpr4 +/+ /Ogr1 +/+ /IL-10 -/- mice (p = 0.002 **) whereas there was no difference in male mice (p = 0.776). In comparison with Gpr4 +/+ /Ogr1 +/+ /IL-10 -/- mice,
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