Orphan G protein-coupled receptor GPRC5B controls macrophage function by facilitating prostaglandin E receptor 2 signaling
Abstract Macrophages express numerous G protein-coupled receptors (GPCRs) that regulate adhesion, migration, and activation, but the function of orphan receptor GPRC5B in macrophages is unknown. Both resident peritoneal and bone marrow-derived macrophages from myeloid-specific GPRC5B-deficient mice...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56713-0 |
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| author | Jeonghyeon Kwon Haruya Kawase Kenny Mattonet Stefan Guenther Lisa Hahnefeld Jamal Shamsara Jan Heering Michael Kurz Sina Kirchhofer Cornelius Krasel Michaela Ulrich Margherita Persechino Sripriya Murthy Cesare Orlandi Christian D. Sadik Gerd Geisslinger Moritz Bünemann Peter Kolb Stefan Offermanns Nina Wettschureck |
| author_facet | Jeonghyeon Kwon Haruya Kawase Kenny Mattonet Stefan Guenther Lisa Hahnefeld Jamal Shamsara Jan Heering Michael Kurz Sina Kirchhofer Cornelius Krasel Michaela Ulrich Margherita Persechino Sripriya Murthy Cesare Orlandi Christian D. Sadik Gerd Geisslinger Moritz Bünemann Peter Kolb Stefan Offermanns Nina Wettschureck |
| author_sort | Jeonghyeon Kwon |
| collection | DOAJ |
| description | Abstract Macrophages express numerous G protein-coupled receptors (GPCRs) that regulate adhesion, migration, and activation, but the function of orphan receptor GPRC5B in macrophages is unknown. Both resident peritoneal and bone marrow-derived macrophages from myeloid-specific GPRC5B-deficient mice show increased migration and phagocytosis, resulting in improved bacterial clearance in a peritonitis model. In other models such as myocardial infarction, increased myeloid cell recruitment has adverse effects. Mechanistically, we found that GPRC5B physically interacts with GPCRs of the prostanoid receptor family, resulting in enhanced signaling through the prostaglandin E receptor 2 (EP2). In GPRC5B-deficient macrophages, EP2-mediated anti-inflammatory effects are diminished, resulting in hyperactivity. Using in silico modelling and docking, we identify residues potentially mediating GPRC5B/EP2 dimerization and show that their mutation results in loss of GPRC5B-mediated facilitation of EP2 signaling. Finally, we demonstrate that decoy peptides mimicking the interacting sequence are able to reduce GPRC5B-mediated facilitation of EP2-induced cAMP signaling in macrophages. |
| format | Article |
| id | doaj-art-64689d6e86354a78ab13b36978b12d29 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-64689d6e86354a78ab13b36978b12d292025-02-09T12:46:19ZengNature PortfolioNature Communications2041-17232025-02-0116112310.1038/s41467-025-56713-0Orphan G protein-coupled receptor GPRC5B controls macrophage function by facilitating prostaglandin E receptor 2 signalingJeonghyeon Kwon0Haruya Kawase1Kenny Mattonet2Stefan Guenther3Lisa Hahnefeld4Jamal Shamsara5Jan Heering6Michael Kurz7Sina Kirchhofer8Cornelius Krasel9Michaela Ulrich10Margherita Persechino11Sripriya Murthy12Cesare Orlandi13Christian D. Sadik14Gerd Geisslinger15Moritz Bünemann16Peter Kolb17Stefan Offermanns18Nina Wettschureck19Department of Pharmacology, Max Planck Institute for Heart and Lung ResearchDepartment of Pharmacology, Max Planck Institute for Heart and Lung ResearchImaging Platform, Max Planck Institute for Heart and Lung ResearchDeep sequencing platform, Max Planck Institute for Heart and Lung ResearchFraunhofer Institute for Translational Medicine and Pharmacology ITMPDepartment of Pharmaceutical Chemistry, University of MarburgFraunhofer Institute for Translational Medicine and Pharmacology ITMPDepartment of Pharmacology and Clinical Pharmacy, University of MarburgDepartment of Pharmacology and Clinical Pharmacy, University of MarburgDepartment of Pharmacology and Clinical Pharmacy, University of MarburgDepartment of Pharmacology and Clinical Pharmacy, University of MarburgDepartment of Pharmaceutical Chemistry, University of MarburgDepartment of Dermatology, Allergy, and Venereology, University of LübeckDepartment of Pharmacology and Physiology, University of Rochester Medical CenterDepartment of Dermatology, Allergy, and Venereology, University of LübeckFraunhofer Institute for Translational Medicine and Pharmacology ITMPDepartment of Pharmacology and Clinical Pharmacy, University of MarburgDepartment of Pharmaceutical Chemistry, University of MarburgDepartment of Pharmacology, Max Planck Institute for Heart and Lung ResearchDepartment of Pharmacology, Max Planck Institute for Heart and Lung ResearchAbstract Macrophages express numerous G protein-coupled receptors (GPCRs) that regulate adhesion, migration, and activation, but the function of orphan receptor GPRC5B in macrophages is unknown. Both resident peritoneal and bone marrow-derived macrophages from myeloid-specific GPRC5B-deficient mice show increased migration and phagocytosis, resulting in improved bacterial clearance in a peritonitis model. In other models such as myocardial infarction, increased myeloid cell recruitment has adverse effects. Mechanistically, we found that GPRC5B physically interacts with GPCRs of the prostanoid receptor family, resulting in enhanced signaling through the prostaglandin E receptor 2 (EP2). In GPRC5B-deficient macrophages, EP2-mediated anti-inflammatory effects are diminished, resulting in hyperactivity. Using in silico modelling and docking, we identify residues potentially mediating GPRC5B/EP2 dimerization and show that their mutation results in loss of GPRC5B-mediated facilitation of EP2 signaling. Finally, we demonstrate that decoy peptides mimicking the interacting sequence are able to reduce GPRC5B-mediated facilitation of EP2-induced cAMP signaling in macrophages.https://doi.org/10.1038/s41467-025-56713-0 |
| spellingShingle | Jeonghyeon Kwon Haruya Kawase Kenny Mattonet Stefan Guenther Lisa Hahnefeld Jamal Shamsara Jan Heering Michael Kurz Sina Kirchhofer Cornelius Krasel Michaela Ulrich Margherita Persechino Sripriya Murthy Cesare Orlandi Christian D. Sadik Gerd Geisslinger Moritz Bünemann Peter Kolb Stefan Offermanns Nina Wettschureck Orphan G protein-coupled receptor GPRC5B controls macrophage function by facilitating prostaglandin E receptor 2 signaling Nature Communications |
| title | Orphan G protein-coupled receptor GPRC5B controls macrophage function by facilitating prostaglandin E receptor 2 signaling |
| title_full | Orphan G protein-coupled receptor GPRC5B controls macrophage function by facilitating prostaglandin E receptor 2 signaling |
| title_fullStr | Orphan G protein-coupled receptor GPRC5B controls macrophage function by facilitating prostaglandin E receptor 2 signaling |
| title_full_unstemmed | Orphan G protein-coupled receptor GPRC5B controls macrophage function by facilitating prostaglandin E receptor 2 signaling |
| title_short | Orphan G protein-coupled receptor GPRC5B controls macrophage function by facilitating prostaglandin E receptor 2 signaling |
| title_sort | orphan g protein coupled receptor gprc5b controls macrophage function by facilitating prostaglandin e receptor 2 signaling |
| url | https://doi.org/10.1038/s41467-025-56713-0 |
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