title: GPR4 deficiency alleviates intestinal inflammation in a mouse model of acute experimental colitis.
abstract: GPR4 is a proton-sensing G protein-coupled receptor that can be activated by extracellular acidosis. It has recently been demonstrated that activation of GPR4 by acidosis increases the expression of numerous inflammatory and stress response genes in vascular endothelial cells (ECs) and also augments EC-leukocyte adhesion. Inhibition of GPR4 by siRNA or small molecule inhibitors reduces endothelial cell inflammation. As acidotic tissue microenvironments exist in many types of inflammatory disorders, including inflammatory bowel disease (IBD), we examined the role of GPR4 in intestinal inflammation using a dextran sulfate sodium (DSS)-induced acute colitis mouse model. We observed that GPR4 mRNA expression was increased in mouse and human IBD tissues when compared to control intestinal tissues. To determine the function of GPR4 in intestinal inflammation, wild-type and GPR4-deficient mice were treated with 3% DSS for 7days to induce acute colitis. Our results showed that the severity of colitis was decreased in GPR4-deficient DSS-treated mice in comparison to wild-type DSS-treated mice. Clinical parameters, macroscopic disease indicators, and histopathological features were less severe in the DSS-treated GPR4-deficient mice than the DSS-treated wild-type mice. Endothelial adhesion molecule expression, leukocyte infiltration, and isolated lymphoid follicle (ILF) formation were reduced in intestinal tissues of DSS-treated GPR4-null mice. Collectively, our results suggest GPR4 provides a pro-inflammatory role in the inflamed gut as the absence of GPR4 ameliorates intestinal inflammation in the acute experimental colitis mouse model.
authors.affiliation: Department of Internal Medicine, Brody School of Medicine, East Carolina University, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Sanderlin
authors.affiliation: Department of Internal Medicine, Brody School of Medicine, East Carolina University, USA.
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Leffler
authors.affiliation: Department of Comparative Medicine, Brody School of Medicine, East Carolina University, USA.
authors.forename: Kvin
authors.initials: K
authors.lastname: Lertpiriyapong
authors.affiliation: Department of Pathology, Brody School of Medicine, East Carolina University, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cai
authors.affiliation: Department of Pathology, Brody School of Medicine, East Carolina University, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Hong
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, USA.
authors.forename: Vasudevan
authors.initials: V
authors.lastname: Bakthavatchalu
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.affiliation: Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, USA.
authors.forename: Joani Zary
authors.initials: JZ
authors.lastname: Oswald
authors.affiliation: Department of Internal Medicine, Brody School of Medicine, East Carolina University, USA.
authors.forename: Calvin R
authors.initials: CR
authors.lastname: Justus
authors.affiliation: Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Krewson
authors.affiliation: Department of Comparative Medicine, Brody School of Medicine, East Carolina University, USA.
authors.forename: Dorcas
authors.initials: D
authors.lastname: O'Rourke
authors.affiliation: Department of Internal Medicine, Brody School of Medicine, East Carolina University, USA; Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, USA. Electronic address: yangl@ecu.edu.
authors.forename: Li V
authors.initials: LV
authors.lastname: Yang
mesh_terms: D000208:Acute Disease; D000818:Animals; D002432:Cecum / Q000378:metabolism / Q000473:pathology; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D015854:Up-Regulation
chemical_list: C517811:GPR4 protein, mouse; D043562:Receptors, G-Protein-Coupled; D016264:Dextran Sulfate
keywords: Acidosis; Endothelial cell; GPR4; Inflammation; Inflammatory bowel disease (IBD)