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bioRxiv · 10.1101/059014

GPR4 Deficiency Alleviates Intestinal Inflammation in a Mouse Model of Inflammatory Bowel Disease

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
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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 IBD using a dextran sulfate sodium (DSS)-induced 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 IBD, 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. Inflammatory gene 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 IBD as the absence of GPR4 ameliorates intestinal inflammation in the acute DSS-induced IBD mouse model.

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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. 2016-06-14. GPR4 Deficiency Alleviates Intestinal Inflammation in a Mouse Model of Inflammatory Bowel Disease. https://doi.org/10.1101/059014

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