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Role of Ph Receptor GPR4 in Inflammatory Bowel Disease

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Role of Ph Receptor GPR4 in Inflammatory Bowel Disease Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2018 The proton-activated receptor GPR4 modulates intestinal inflammation Wang, Yu ; de Vallière, Cheryl ; Imenez Silva, Pedro H ; Leonardi, Irina ; Gruber, Sven ; Gerstgrasser, Alexandra ; Melhem, Hassan ; Weber, Achim ; Leucht, Katharina ; Wolfram, Lutz ; Hausmann, Martin ; Krieg, Carsten ; Thomasson, Koray ; Boyman, Onur ; Frey-Wagner, Isabelle ; Rogler, Gerhard ; Wagner, Carsten A Abstract: BACKGROUND AND AIMS: During active inflammation tissue intraluminal intestinal pH is decreased in patients with inflammatory bowel disease (IBD). Acidic pH may play a role in IBD patho- physiology. Recently, proton sensing G-protein coupled receptors were identified, including GPR4, OGR1 (GPR68), and TDAG8 (GPR65). We investigated whether GPR4 is involved in intestinal inflammation. METHODS: The role of GPR4 was assessed in murine colitis models: chronic dextran sulphate sodium (DSS) administration and by crossbreeding into an IL-10 deficient background for development of sponta- neous colitis. Colitis severity was assessed by body weight, colonoscopy, colon length, histological score, cytokine mRNA expression, and myeloperoxidase (MPO) activity. In the spontaneous Il-10-/- colitis model, the incidence of rectal prolapse and characteristics of lamina propria leukocytes (LPLs) were an- alyzed. RESULTS: Gpr4-/- mice showed reduced body weight loss and histology score after induction of chronic DSS colitis. In Gpr4-/- /Il-10-/- double knock-outs the onset and progression of rectal prolapse were significantly delayed and mitigated compared to Gpr4+/+ /Il-10-/- mice. Double knock-out mice showed lower histology scores, MPO activity, CD4 + T-helper cell infiltration, IFN-฀, iNOS, MCP-1 (CCL2), CXCL1 and CXCL2 expression compared to controls. In colon, GPR4 mRNA was detected in endothelial cells, some smooth muscle cells, and some macrophages. CONCLUSION: Absence of GPR4 ameliorates colitis in IBD animal models indicating an important regulatory rolein mucosal inflammation, thus providing a new link between tissue pH and the immune system. Therapeutic inhibition of GPR4 may be beneficial for the treatment of IBD. DOI: https://doi.org/10.1093/ecco-jcc/jjx147 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-144879 Journal Article Accepted Version Originally published at: Wang, Yu; de Vallière, Cheryl; Imenez Silva, Pedro H; Leonardi, Irina; Gruber, Sven; Gerstgrasser, Alexandra; Melhem, Hassan; Weber, Achim; Leucht, Katharina; Wolfram, Lutz; Hausmann, Martin; Krieg, Carsten; Thomasson, Koray; Boyman, Onur; Frey-Wagner, Isabelle; Rogler, Gerhard; Wagner, Carsten A (2018). The proton-activated receptor GPR4 modulates intestinal inflammation. Journal of Crohn’s Colitis, 12(3):355-368. DOI: https://doi.org/10.1093/ecco-jcc/jjx147 Gpr4 modulates colitis 1 2 The proton-activated receptor 3 4 GPR4 modulates intestinal inflammation 5 6 Yu Wang1,2*, Cheryl de Vallière1*, Pedro H. Imenez Silva2, Irina Leonardi1, Sven 7 Gruber1,2, Alexandra Gerstgrasser1, Hassan Melhem1, Achim Weber3, 8 Katharina Leucht1, Lutz Wolfram1, Martin Hausmann1, Carsten Krieg4,5, Koray 9 Thomasson4, Onur Boyman4,6, Isabelle Frey-Wagner1, Gerhard Rogler1,2§, 10 Carsten A. Wagner2§. 11 12 * Yu Wang and Cheryl de Valliere contributed equally to this work 13 § Gerhard Rogler and Carsten A. Wagner share last authorship 14 15 1 Department of Gastroenterology and Hepatology, University Hospital Zurich, 16 Zurich, Switzerland. 17 2 Institute of Physiology, University of Zurich, Zurich, Switzerland. 18 3 Institute of Surgical Pathology, University Hospital Zurich, Zurich, 19 Switzerland 20 4 Laboratory of Applied Immunobiology, University of Zurich, Zurich, 21 Switzerland. 22 5 current address: Institute of Experimental Immunology, University of Zurich, 23 Zurich, Switzerland. 24 6 Department of Immunology, University Hospital Zurich, University of Zurich, 25 Zurich, Switzerland. 26 27 SHORT TITLE: Gpr4 modulates colitis 28 29 Corresponding authors: 30 Prof. Dr. Carsten A. Wagner Prof. Dr. Dr. Gerhard Rogler University of Zurich Department of Gastroenterology and Institute of Physiology Hepatology Winterthurerstrasse 190 University Hospital Zurich CH 8057 Zürich, Switzerland Rämistrasse 100 Tel.: +41-44-5355023 CH-8091 Zurich Fax: +41-44-6356814 Switzerland. E-mail: [email protected] Tel.: +41 (0)44 255 95 19 Fax: +41 (0)44 255 94 97 Email: [email protected] 31 Gpr4 modulates colitis 32 33 34 35 Gpr4 modulates colitis 36 Abstract 37 38 BACKGROUND AND AIMS: During active inflammation tissue intraluminal 39 intestinal pH is decreased in patients with inflammatory bowel disease (IBD). 40 Acidic pH may play a role in IBD pathophysiology. Recently, proton sensing 41 G-protein coupled receptors were identified, including GPR4, OGR1 (GPR68), 42 and TDAG8 (GPR65). We investigated whether GPR4 is involved in intestinal 43 inflammation. 44 METHODS: The role of GPR4 was assessed in murine colitis models: chronic 45 dextran sulphate sodium (DSS) administration and by crossbreeding into an 46 IL-10 deficient background for development of spontaneous colitis. Colitis 47 severity was assessed by body weight, colonoscopy, colon length, histological 48 score, cytokine mRNA expression, and myeloperoxidase (MPO) activity. In the 49 spontaneous Il-10-/- colitis model, the incidence of rectal prolapse and 50 characteristics of lamina propria leukocytes (LPLs) were analyzed. 51 RESULTS: Gpr4-/- mice showed reduced body weight loss and histology score 52 after induction of chronic DSS colitis. In Gpr4-/- /Il-10-/- double knock-outs the 53 onset and progression of rectal prolapse were significantly delayed and 54 mitigated compared to Gpr4+/+ /Il-10-/- mice. Double knock-out mice showed 55 lower histology scores, MPO activity, CD4+ T-helper cell infiltration, IFN-γ, 56 iNOS, MCP-1 (CCL2), CXCL1 and CXCL2 expression compared to controls. 57 In colon, GPR4 mRNA was detected in endothelial cells, some smooth muscle 58 cells, and some macrophages. 59 CONCLUSION: Absence of GPR4 ameliorates colitis in IBD animal models 60 indicating an important regulatory rolein mucosal inflammation, thus providing 61 a new link between tissue pH and the immune system. Therapeutic inhibition 62 of GPR4 may be beneficial for the treatment of IBD. 63 64 Key Words: G-protein coupled receptor; pH receptors; GPR4; IBD; animal 65 model. Gpr4 modulates colitis 66 67 68 Abbreviations: CCL20, chemokine (C-C motif) ligand 20; CD, Crohn's 69 disease; CD31, cluster of differentiation 31; COX-2, 70 prostaglandin-endoperoxide synthase 2; CXCL1, chemokine (C-X-C motif) 71 ligand 1; CXCL2, chemokine (C-X-C motif) ligand 2; DSS, dextran sulphate 72 sodium; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GPCR, 73 G-protein coupled receptor; GPR4, G protein coupled receptor 4; H&E, 74 hematoxylin and eosin; IBD, inflammatory bowel disease; ICAM-1, intercellular 75 adhesion molecule 1; IFN-γ, interferon gamma; IL-10, interleukin 10; IL-18, 76 interleukin 18; IL-6, interleukin 6; iNOS, nitric oxide synthase 2; LPLs, lamina 77 propria leukocytes; MCP-1, chemokine (C-C motif) ligand 2, CCL2; MEICS, 78 murine endoscopic index of colitis severity, MPO, myeloperoxidase; OGR1, 79 ovarian cancer G protein coupled receptor 68 (also Gpr68); OR, odds ratio; 80 PBS, phosphate buffered saline; RT-PCR, reverse transcription polymerase 81 chain reaction; α-SMA, α-smooth muscle actin; SELE, selectin, endothelial cell; 82 TDAG8, T-Cell Death-Activated Gene 8 (also known as G-protein coupled 83 receptor Gpr65); TNF, tumor necrosis factor; UC, ulcerative colitis; VCAM1, 84 vascular cell adhesion molecule 1. 85 86 87 Gpr4 modulates colitis 88 Introduction 89 90 A local acidification in the gut lumen as well as in the mucosa has been 91 observed during intestinal inflammation and implicated in the pathogenesis 92 and progression of inflammatory bowel disease (IBD). Fallingborg et al. 93 reported that intraluminal colonic pH values in the proximal parts of the colon 94 were significnatly lower in patients with active ulcerative colitis (UC) than in 95 normal subjects (lowest values 2.3, 2.9, and 3.4) 1. Nugent and coworkers also 96 reported a decrease of colonic luminal pH values to less than 5.5 in two out of 97 six patients with active UC 2. Also in patients with active Crohn’s disease (CD) 98 three out of four CD patients investigated had decreased pH values in the 99 proximal colon (pH 5.3) and distal colon (pH 5.3) as compared to normal 100 controls (pH 6.8) 2. While there is still some controversy about the range of the 101 intestinal luminal pH in IBD patients 3,4, it is widely accepted that inflammation 102 is accompanied by tissue acidification due to hypoxia and excessive 103 production and insufficient elimination of glycolytic metabolites. This indicates 104 that luminal and tissue pH is decreased during active IBD. The 105 (patho)physiological impact of these observations, however, has remained 106 incompletely understood to date. 107 108 G protein-coupled receptors (GPCR) play an important role in regulating 109 intestinal functions and have been implicated in the development and course 110 of IBD 5-6. Only recently, we found that the GPCR OGR1 (Ovarian cancer 111 G-protein-coupled receptor 1, GPR68) plays a role in IBD and that genetic 112 deletion of OGR1 partially prevents the development of colitis in the IL-10 113 deficient IBD mouse model 7. The effects
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