The Proton-activated Receptor GPR4 Modulates Intestinal Inflammation

Abstract

Absence of GPR4 ameliorates colitis in IBD animal models, indicating an important regulatory role in 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.

Dietary Nondigestible Polysaccharides Ameliorate Colitis by Improving Gut Microbiota and CD4+ Differentiation, as Well as Facilitating M2 Macrophage Polarization

“…In contrast with mice in the IL‐10 −/− group, IL‐10 −/− mice were protected from colonic mucosa inflammation with less infiltration of inflammatory cells, lower mean inflammation scores, and a partially restored glandular and goblet cell architecture by MF treatment (Figure B and C). Subsequently, we detected the colonic MPO concentration, which is now widely accepted as a marker to quantify the degree of the accumulation of inflammatory cells, especially neutrophils . Notably, increased concentrations of MPO in IL‐10 −/− mice were reduced by MF treatment (Figure D).…”

“…Subsequently, we detected the colonic MPO concentration, which is now widely accepted as a marker to quantify the degree of the accumulation of inflammatory cells, especially neutrophils. 15 Notably, increased concentrations of MPO in IL-10 −/− mice were reduced by MF treatment ( Figure 1D). It has been shown that chronic inflammation in the colon of IL-10 −/− mice is mainly mediated by Th1 and Th17 cells.…”

“…13 In a previous study, we demonstrated that intestinal SCFAs derived from the microbiota by dietary nondigestible polysaccharides treatment ameliorated intestinal epithelial barrier dysfunction in IL-10 −/− mice. 14 Moreover, macrophages are essential for intestinal homeostasis and the pathology of IBD 15 ; however, the relationship between inflammation in LP and macrophage polarization after dietary nondigestible polysaccharides was not studied. In this study, we mainly investigated the detailed therapeutic mechanism of dietary nondigestible polysaccharides in IL-10 −/− mice with spontaneous chronic colitis.…”

Pharmacological inhibition of GPR4 remediates intestinal inflammation in a mouse colitis model

“…One such family of GPCRs are the protonsensing GPCRs, which consist of GPR4, GPR65 (TDAG8), and GPR68 (OGR1) (Justus et al, 2013;Justus et al, 2017;Ludwig et al, 2003;Sanderlin et al, 2015). These receptors have been implicated in the modulation of intestinal inflammation (de Valliere et al, 2015;Lassen et al, 2016;Sanderlin et al, 2017;Wang et al, 2018). Studies have shown GPR4 is responsible for acidosis-induced endothelial cell inflammation and can functionally increase leukocyte adhesion with endothelial cells (Chen et al, 2011;Dong et al, 2017;Dong et al, 2013;Tobo et al, 2015).…”

“…Studies have shown GPR4 is responsible for acidosis-induced endothelial cell inflammation and can functionally increase leukocyte adhesion with endothelial cells (Chen et al, 2011;Dong et al, 2017;Dong et al, 2013;Tobo et al, 2015). GPR4 genetic deletion in mice reduces intestinal inflammation and mucosal leukocyte infiltration in both inducible and spontaneous colitis mouse models Wang et al, 2018). However, the effects of pharmacological modulators of protonsensing GPCRs in intestinal inflammation have not been investigated.…”