Orphan G protein-coupled receptor GPRC5B controls macrophage function by facilitating prostaglandin E receptor 2 signaling
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.
Authors
- Sina B. Kirchhofer (ORCID: https://orcid.org/0000-0001-6285-9054)
- Michael Kurz (ORCID: https://orcid.org/0000-0003-0326-2404)
- Lisa Hahnefeld (ORCID: https://orcid.org/0000-0002-0382-5695)
- Jeonghyeon Kwon (ORCID: https://orcid.org/0009-0000-5818-0110)
- Jamal Shamsara (ORCID: https://orcid.org/0000-0002-6162-6037)
- Margherita Persechino (ORCID: https://orcid.org/0000-0003-1539-7621)
- Jan Heering (ORCID: https://orcid.org/0000-0002-4922-1993)
- Moritz Buenemann (ORCID: https://orcid.org/0000-0002-2259-4378)
- Nina Wettschureck (ORCID: https://orcid.org/0000-0001-6858-1460)
- Kenny Mattonet (ORCID: https://orcid.org/0000-0002-9705-8086)
- Peter Kolb (ORCID: https://orcid.org/0000-0003-4089-614X)
- Cesare Orlandi (ORCID: https://orcid.org/0000-0002-4992-9350)
- Stefan Günther (ORCID: https://orcid.org/0000-0002-5594-4549)
- Gerd Geißlinger (ORCID: https://orcid.org/0000-0003-0552-7488)
- Cornelius Krasel (ORCID: https://orcid.org/0000-0001-8309-8696)
- Sripriya Murthy (ORCID: https://orcid.org/0000-0003-3612-7532)
- Haruya Kawase (ORCID: https://orcid.org/0000-0002-8927-0896)
- Christian D. Sadik (ORCID: https://orcid.org/0000-0001-6701-048X)
- Stefan Offermanns (ORCID: https://orcid.org/0000-0001-8676-6805)
- Michaela Ulrich (ORCID: https://orcid.org/0009-0007-1190-4215)
Institutions
- Goethe University Frankfurt (DE)
- Philipps University of Marburg (DE)
- University of Rochester Medical Center (US)
- Max Planck Institute for Heart and Lung Research (DE)
- Fraunhofer Institute for Translational Medicine and Pharmacology (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-07
- DOI
- https://doi.org/10.1038/s41467-025-56713-0
- Citations
- 7
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- Deutsche Forschungsgemeinschaft