TY - JOUR
T1 - GPR4 deficiency alleviates intestinal inflammation in a mouse model of acute experimental colitis
AU - Sanderlin, Edward J.
AU - Leffler, Nancy R.
AU - Lertpiriyapong, Kvin
AU - Cai, Qi
AU - Hong, Heng
AU - Bakthavatchalu, Vasudevan
AU - Fox, James G.
AU - Oswald, Joani Zary
AU - Justus, Calvin R.
AU - Krewson, Elizabeth A.
AU - O'Rourke, Dorcas
AU - Yang, Li V.
N1 - Funding Information:
We would like to thank Connor Hart and Lixue Dong for their excellent technical assistance. Additionally, we would like to thank Dr. Owen N. Witte for providing the GPR4 knockout mouse strain and Dr. Mary J. Thomassen's lab for generously sharing equipment and reagents. This study was supported in part by National Institutes of Health (1R15DK109484-01, to L.V.Y. and K.L.), Brody Brothers Endowment Fund (# 213149, to L.V.Y. and K.L.), American Heart Association (# 11SDG5390021, to L.V.Y.), and Vidant Cancer Research and Education Fund (to L.V.Y.).
Publisher Copyright:
© 2016 Elsevier B.V.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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.
AB - 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.
KW - Acidosis
KW - Endothelial cell
KW - GPR4
KW - Inflammation
KW - Inflammatory bowel disease (IBD)
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UR - http://www.scopus.com/inward/citedby.url?scp=85003906057&partnerID=8YFLogxK
U2 - 10.1016/j.bbadis.2016.12.005
DO - 10.1016/j.bbadis.2016.12.005
M3 - Article
C2 - 27940273
AN - SCOPUS:85003906057
SN - 0925-4439
VL - 1863
SP - 569
EP - 584
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 2
ER -