G Protein-coupled pH-sensing Receptor OGR1 Is a Regulator of Intestinal Inflammation

Vallière, Cheryl de; Wang, Yu; Eloranta, Jyrki J.; Vidal, Solange; Clay, Ieuan; Spalinger, Marianne R.; Tcymbarevich, Irina; Terhalle, Anne; Ludwig, Marie-Gabrielle; Suply, Thomas; Fried, Michael; Kullak‐Ublick, Gerd A.; Frey-Wagner, Isabelle; Scharl, Michael; Seuwen, Klaus; Wagner, Carsten A.; Rogler, Gerhard

doi:10.1097/mib.0000000000000375

Cited by 59 publications

(115 citation statements)

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“…Our earlier work has shown that OGR1 mRNA is expressed in human small intestine and colon (6). We notably observed that OGR1 expression is significantly higher in human colon biopsies from CD and UC patient groups compared with the non-IBD control group.…”

Section: Discussionmentioning

confidence: 56%

“…Therefore, it is expected that chronic activation of OGR1 may exacerbate tissue damage in IBD, which may be sustained further by increased release of inflammatory mediators from myeloid cells exposed to acidic pH (6). Indeed, we could show that deficiency of OGR1 protects female mice from disease manifestations in a murine model of IBD (6).…”

Section: Discussionmentioning

confidence: 92%

“…One of these GPCRs, ovarian cancer GPCR 1 (OGR1; alias GPR68), is expressed in the intestinal epithelium and upregulated during inflammation (6). Earlier work has established that this receptor can trigger calcium release from intracellular stores, activate PKC, and stimulate SRF-dependent promoter activity, potentially linking it to epithelial function (21,28).…”

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confidence: 98%

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The pH-sensing receptor OGR1 improves barrier function of epithelial cells and inhibits migration in an acidic environment

Vallière

Vidal

Clay

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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The pH-sensing receptor ovarian cancer G protein-coupled receptor 1 (OGR1; GPR68) is expressed in the gut. Inflammatory bowel disease is typically associated with a decrease in local pH, which may lead to altered epithelial barrier function and subsequent gastrointestinal repair involving epithelial cell adhesion and migration. As the mechanisms underlying the response to pH changes are not well understood, we have investigated OGR1-mediated, pH-dependent signaling pathways in intestinal epithelial cells. Caco-2 cells stably overexpressing OGR1 were created and validated as tools to study OGR1 signaling. Barrier function, migration, and proliferation were measured using electric cell-substrate impedance-sensing technology. Localization of the tight junction proteins zonula occludens protein 1 and occludin and the rearrangement of cytoskeletal actin were examined by confocal microscopy. Paracellular permeability and protein and gene expression analysis using DNA microarrays were performed on filter-grown Caco-2 monolayers. We report that an acidic pH shift from pH 7.8 to 6.6 improved barrier function and stimulated reorganization of filamentous actin with prominent basal stress fiber formation. Cell migration and proliferation during in vitro wound healing were inhibited. Gene expression analysis revealed significant upregulation of genes related to cytoskeleton remodeling, cell adhesion, and growth factor signaling. We conclude that acidic extracellular pH can have a signaling function and impact the physiology of intestinal epithelial cells. The deconstruction of OGR1-dependent signaling may aid our understanding of mucosal inflammation mechanisms.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 98%

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The pH-sensing receptor OGR1 improves barrier function of epithelial cells and inhibits migration in an acidic environment

Vallière

Vidal

Clay

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Ovarian cancer G protein-coupled receptor 1 (OGR1) has recently been implicated as a regulator of intestinal inflammation through the control of macrophage inflammatory responses [69]. Using IL-10 −/− (knockout) mice for the development of chronic spontaneous intestinal inflammation, OGR1 deficiency alleviated mucosal inflammation when compared to control mice.…”

Section: Discussionmentioning

confidence: 99%

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

Sanderlin

Leffler

Lertpiriyapong

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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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.

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“…The effect of pH on the two biological processes may constitute a balancing act integrating adaptation to the environment as well as sexual reproduction. Because in mammals, pH or proton sensing GPCRs were discovered (Tomura et al, 2005;de Valliere et al, 2015), and the use of receptors of the GPCR family for sensing environmental cues is conserved among eukaryotes; it is likely that fungi exploit similar mechanisms. In this context, it would be interesting to investigate the involvement of fungal GPCRs, such as Ste2 in S. cerevisiae (Kim et al, 2012), in pH sensing and adaptation mechanisms.…”

Section: Sensing Of Physical Cuesmentioning

confidence: 99%

Fungal sensing of host environment

Braunsdorf

Mailänder-Sánchez²,

Schaller

2016

Cellular Microbiology

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Summary To survive inside a host, fungi have to adapt to a changing and often hostile environment and therefore need the ability to recognize what is going on around them. To adapt to different host niches, they need to sense external conditions such as temperature, pH and to recognize specific host factors. The ability to respond to physiological changes inside the host, independent of being in a commensal, pathogenic or even symbiotic context, implicates mechanisms for sensing of specific host factors. Because the cell wall is constantly in contact with the surrounding, fungi express receptors on the surface of their cell wall, such as pheromone receptors, which have important roles, besides mediating chemotropism for mating. We are not restricting the discussion to the human host because the receptors and mechanisms used by different fungal species to sense their environment are often similar even for plant pathogens. Furthermore, the natural habitat of opportunistic pathogenic fungi with the potential to cause infection in a human host is in soil and on plants. While the hosts' mechanisms of sensing fungal pathogens have been addressed in the literature, the focus of this review is to fill the gap, giving an overview on fungal sensing of a host‐(ile) environment. Expanding our knowledge on host–fungal interactions is extremely important to prevent and treat diseases of pathogenic fungi, which are important issues in human health and agriculture but also to understand the delicate balance of fungal symbionts in our ecosystem.

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G Protein-coupled pH-sensing Receptor OGR1 Is a Regulator of Intestinal Inflammation

Abstract: Article first published online 7 April 2015.Supplemental Digital Content is Available in the Text.

Cited by 59 publications

References 59 publications

The pH-sensing receptor OGR1 improves barrier function of epithelial cells and inhibits migration in an acidic environment

The pH-sensing receptor OGR1 improves barrier function of epithelial cells and inhibits migration in an acidic environment

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

Fungal sensing of host environment

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