GPR4 deficiency alleviates intestinal inflammation in a mouse model of acute experimental colitis

Edward J. Sanderlin, Nancy R. Leffler, Kvin Lertpiriyapong, Qi Cai, Heng Hong, Vasudevan Bakthavatchalu, James G. Fox, Joani Zary Oswald, Calvin R. Justus, Elizabeth A. Krewson, Dorcas O'Rourke, Li V. Yang

Research output: Contribution to journalArticle

15 Scopus citations

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 7 days 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.

Original languageEnglish (US)
Pages (from-to)569-584
Number of pages16
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1863
Issue number2
DOIs
StatePublished - Feb 1 2017
Externally publishedYes

Keywords

  • Acidosis
  • Endothelial cell
  • GPR4
  • Inflammation
  • Inflammatory bowel disease (IBD)

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Fingerprint Dive into the research topics of 'GPR4 deficiency alleviates intestinal inflammation in a mouse model of acute experimental colitis'. Together they form a unique fingerprint.

  • Cite this

    Sanderlin, E. J., Leffler, N. R., Lertpiriyapong, K., Cai, Q., Hong, H., Bakthavatchalu, V., Fox, J. G., Oswald, J. Z., Justus, C. R., Krewson, E. A., O'Rourke, D., & Yang, L. V. (2017). GPR4 deficiency alleviates intestinal inflammation in a mouse model of acute experimental colitis. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1863(2), 569-584. https://doi.org/10.1016/j.bbadis.2016.12.005