27 Oct pH Sensing Molecules May Play a Role in Initiating Inflammatory Bowel Disorders
MedicalResearch.com Interview with:
Cheryl de Valliere, PhD
University Hospital Zurich
Division of Gastroenterology and Hepatology
Gerhard Rogler, Jesus Cosin Roger, Pedro A. Ruiz
MedicalResearch.com: What is the background for this study?
Response: Inflammatory Bowel Disease (IBD), including ulcerative colitis and Crohn’s disease, gives rise to chronic relapsing inflammation of the gastrointestinal (GI) tract, resulting in a disruption of the epithelial barrier function and exacerbated innate and adaptive immune responses. One of the most important features under these inflammatory conditions is the presence of hypoxic areas where oxygen levels are lower than in normal tissue. It has been widely reported that the main transcription factor regulating cellular responses to hypoxia, hypoxia inducible factor (HIF)-1, is significantly induced in patients with IBD compared with healthy subjects. Furthermore, hypoxia is not only linked to inflammation, but also influences the local tissue pH, leading to an reduction of the pH in the inflamed mucosa compared with the non-inflamed one.
A family of pH-sensing G-protein coupled receptors (GPCRs), including the receptor T-cell death-associated gene 8 (TDAG8) and the ovarian cancer G-protein coupled receptor 1 (OGR1 or GPR68), play an important role in physiological pH homeostasis. At low extracellular pH, second messenger signaling pathways are activated by protons binding to the histidine residues located on the extracellular region of the receptor. Recent studies have reported a link between IBD and this family of pH-sensing receptors. Indeed, TDAG8 has been identified as an IBD risk gene and we have previously reported an increased expression of OGR1 in patients with IBD compared with healthy subjects.
To better understand the basic mucosal inflammatory mechanisms, and foster the development of new treatment options (e.g. pH receptor blockers and OGR1 antagonists) for chronic mucosal inflammatory diseases, we investigated the effects of hypoxia on pH-sensing OGR1 in the intestinal mucosa and associated cells.
MedicalResearch.com: What are the main findings?
Response: Our results show that hypoxia induces the expression of OGR1 (GPR68) in monocytes/macrophages and intestinal epithelial cells, which is further enhanced in monocytes/macrophages at acidic pH or by tumor necrosis factor treatment. Furthermore, OGR1 expression is also significantly induced in the intestinal mucosa of both healthy subjects and IBD patients after 3 hours under hypoxic conditions. Importantly, in this study we have shown for the first time that HIF-1α can bind to the OGR1 promoter under hypoxia, identifying OGR1 as a direct target gene for HIF-1α.
MedicalResearch.com: What should clinicians and patients take away from your report?
Response: Our earlier studies proposed a role for OGR1 in the development of mucosal inflammation, showing that accumulation of extracellular protons promotes the modulation of cellular responses in monocytes/macrophages and intestinal epithelial cells, such as F-actin stress fiber formation and tightening of the epithelial barrier. In this study, our results demonstrate that an acidic environment enhances hypoxia-induced expression of OGR1, leading to alterations in epithelial barrier function and innate immune responses, and support a role for OGR1 in the pathogenesis of IBD.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: The results obtained in this study strongly suggest that OGR1 and subsequent pH-sensing activity play an important role in the onset of mucosal inflammation. Therefore, we propose that this pH receptor may be considered as a potential therapeutic target for the treatment of IBD. Further investigations should be performed to elucidate whether the use of small molecule modulators of OGR1 could reduce the inflammation in IBD patients. The modulation of the sensing activity of GPCRs could also provide novel therapeutic approaches for the treatment of a variety of pathologies where GPCRs are also involved, such as cancer, cardiovascular disease, and Alzheimer’s disease.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
Hypoxia Positively Regulates the Expression of pH-Sensing G-Protein–Coupled Receptor OGR1 (GPR68)
de Vallière, Cheryl et al.
Cellular and Molecular Gastroenterology and Hepatology , Volume 2 , Issue 6 , 796 – 810
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