Cell-Type-Specific Effects of the Ovarian Cancer G-Protein Coupled Receptor (OGR1) on Inflammation and Fibrosis; Potential Implications for Idiopathic Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is a disease characterized by irreversible lung scarring. The pathophysiology is not fully understood, but the working hypothesis postulates that a combination of epithelial injury and myofibroblast differentiation drives progressive pulmonary fibrosis. We previou...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-08-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/16/2540 |
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| author | David J. Nagel Ashley R. Rackow Wei-Yao Ku Tyler J. Bell Patricia J. Sime Robert Matthew Kottmann |
| author_facet | David J. Nagel Ashley R. Rackow Wei-Yao Ku Tyler J. Bell Patricia J. Sime Robert Matthew Kottmann |
| author_sort | David J. Nagel |
| collection | DOAJ |
| description | Idiopathic pulmonary fibrosis (IPF) is a disease characterized by irreversible lung scarring. The pathophysiology is not fully understood, but the working hypothesis postulates that a combination of epithelial injury and myofibroblast differentiation drives progressive pulmonary fibrosis. We previously demonstrated that a reduction in extracellular pH activates latent TGF-β1, and that TGF-β1 then drives its own activation, creating a feed-forward mechanism that propagates myofibroblast differentiation. Given the important roles of extracellular pH in the progression of pulmonary fibrosis, we sought to identify whether pH mediates other cellular phenotypes independent of TGF-β1. Proton-sensing G-protein coupled receptors are activated by acidic environments, but their role in fibrosis has not been studied. Here, we report that the Ovarian Cancer G-Protein Coupled Receptor1 (OGR1 or GPR68) has dual roles in both promoting and mitigating pulmonary fibrosis. We demonstrate that OGR1 protein expression is significantly reduced in lung tissue from patients with IPF and that TGF-β1 decreases OGR1 expression. In fibroblasts, OGR1 inhibits myofibroblast differentiation and does not contribute to inflammation. However, in epithelial cells, OGR1 promotes epithelial to mesenchymal transition (EMT) and inflammation. We then demonstrate that sub-cellular localization and alternative signaling pathways may be responsible for the differential effect of OGR1 in each cell type. Our results suggest that strategies to selectively target OGR1 expression may represent a novel therapeutic strategy for pulmonary fibrosis. |
| first_indexed | 2024-03-09T09:59:12Z |
| format | Article |
| id | doaj.art-3e6e3950c7e34610a09513be7ac00a77 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T09:59:12Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-3e6e3950c7e34610a09513be7ac00a772023-12-01T23:33:28ZengMDPI AGCells2073-44092022-08-011116254010.3390/cells11162540Cell-Type-Specific Effects of the Ovarian Cancer G-Protein Coupled Receptor (OGR1) on Inflammation and Fibrosis; Potential Implications for Idiopathic Pulmonary FibrosisDavid J. Nagel0Ashley R. Rackow1Wei-Yao Ku2Tyler J. Bell3Patricia J. Sime4Robert Matthew Kottmann5Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center, Rochester, NY 14642, USALaboratory Medicine, Department of Pathology, Division of Clinical Chemistry, Johns Hopkins University, Baltimore, MD 21287, USABMW of North America, Woodcliff Lake, NJ 07675, USADepartment of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USADepartment of Medicine, Virginia Commonwealth University Health System, Richmond, VA 23298, USADepartment of Medicine, Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center, Rochester, NY 14642, USAIdiopathic pulmonary fibrosis (IPF) is a disease characterized by irreversible lung scarring. The pathophysiology is not fully understood, but the working hypothesis postulates that a combination of epithelial injury and myofibroblast differentiation drives progressive pulmonary fibrosis. We previously demonstrated that a reduction in extracellular pH activates latent TGF-β1, and that TGF-β1 then drives its own activation, creating a feed-forward mechanism that propagates myofibroblast differentiation. Given the important roles of extracellular pH in the progression of pulmonary fibrosis, we sought to identify whether pH mediates other cellular phenotypes independent of TGF-β1. Proton-sensing G-protein coupled receptors are activated by acidic environments, but their role in fibrosis has not been studied. Here, we report that the Ovarian Cancer G-Protein Coupled Receptor1 (OGR1 or GPR68) has dual roles in both promoting and mitigating pulmonary fibrosis. We demonstrate that OGR1 protein expression is significantly reduced in lung tissue from patients with IPF and that TGF-β1 decreases OGR1 expression. In fibroblasts, OGR1 inhibits myofibroblast differentiation and does not contribute to inflammation. However, in epithelial cells, OGR1 promotes epithelial to mesenchymal transition (EMT) and inflammation. We then demonstrate that sub-cellular localization and alternative signaling pathways may be responsible for the differential effect of OGR1 in each cell type. Our results suggest that strategies to selectively target OGR1 expression may represent a novel therapeutic strategy for pulmonary fibrosis.https://www.mdpi.com/2073-4409/11/16/2540pulmonary fibrosisOGR1 (GPR68)fibroblastepithelial cellGPCRTGFβ signaling |
| spellingShingle | David J. Nagel Ashley R. Rackow Wei-Yao Ku Tyler J. Bell Patricia J. Sime Robert Matthew Kottmann Cell-Type-Specific Effects of the Ovarian Cancer G-Protein Coupled Receptor (OGR1) on Inflammation and Fibrosis; Potential Implications for Idiopathic Pulmonary Fibrosis Cells pulmonary fibrosis OGR1 (GPR68) fibroblast epithelial cell GPCR TGFβ signaling |
| title | Cell-Type-Specific Effects of the Ovarian Cancer G-Protein Coupled Receptor (OGR1) on Inflammation and Fibrosis; Potential Implications for Idiopathic Pulmonary Fibrosis |
| title_full | Cell-Type-Specific Effects of the Ovarian Cancer G-Protein Coupled Receptor (OGR1) on Inflammation and Fibrosis; Potential Implications for Idiopathic Pulmonary Fibrosis |
| title_fullStr | Cell-Type-Specific Effects of the Ovarian Cancer G-Protein Coupled Receptor (OGR1) on Inflammation and Fibrosis; Potential Implications for Idiopathic Pulmonary Fibrosis |
| title_full_unstemmed | Cell-Type-Specific Effects of the Ovarian Cancer G-Protein Coupled Receptor (OGR1) on Inflammation and Fibrosis; Potential Implications for Idiopathic Pulmonary Fibrosis |
| title_short | Cell-Type-Specific Effects of the Ovarian Cancer G-Protein Coupled Receptor (OGR1) on Inflammation and Fibrosis; Potential Implications for Idiopathic Pulmonary Fibrosis |
| title_sort | cell type specific effects of the ovarian cancer g protein coupled receptor ogr1 on inflammation and fibrosis potential implications for idiopathic pulmonary fibrosis |
| topic | pulmonary fibrosis OGR1 (GPR68) fibroblast epithelial cell GPCR TGFβ signaling |
| url | https://www.mdpi.com/2073-4409/11/16/2540 |
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