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Orphan G protein-coupled receptor GPRC5B controls macrophage function by facilitating prostaglandin E receptor 2 signaling

Author

Listed:
  • Jeonghyeon Kwon

    (Max Planck Institute for Heart and Lung Research)

  • Haruya Kawase

    (Max Planck Institute for Heart and Lung Research)

  • Kenny Mattonet

    (Max Planck Institute for Heart and Lung Research)

  • Stefan Guenther

    (Max Planck Institute for Heart and Lung Research)

  • Lisa Hahnefeld

    (Fraunhofer Institute for Translational Medicine and Pharmacology ITMP
    Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD
    Institute of Clinical Pharmacology)

  • Jamal Shamsara

    (University of Marburg)

  • Jan Heering

    (Fraunhofer Institute for Translational Medicine and Pharmacology ITMP
    Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD)

  • Michael Kurz

    (University of Marburg)

  • Sina Kirchhofer

    (University of Marburg)

  • Cornelius Krasel

    (University of Marburg)

  • Michaela Ulrich

    (University of Marburg)

  • Margherita Persechino

    (University of Marburg)

  • Sripriya Murthy

    (University of Lübeck)

  • Cesare Orlandi

    (University of Rochester Medical Center)

  • Christian D. Sadik

    (University of Lübeck)

  • Gerd Geisslinger

    (Fraunhofer Institute for Translational Medicine and Pharmacology ITMP
    Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD
    Institute of Clinical Pharmacology)

  • Moritz Bünemann

    (University of Marburg)

  • Peter Kolb

    (University of Marburg)

  • Stefan Offermanns

    (Max Planck Institute for Heart and Lung Research
    Goethe-University Frankfurt)

  • Nina Wettschureck

    (Max Planck Institute for Heart and Lung Research
    Goethe-University Frankfurt)

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.

Suggested Citation

  • Jeonghyeon Kwon & Haruya Kawase & Kenny Mattonet & Stefan Guenther & Lisa Hahnefeld & Jamal Shamsara & Jan Heering & Michael Kurz & Sina Kirchhofer & Cornelius Krasel & Michaela Ulrich & Margherita Pe, 2025. "Orphan G protein-coupled receptor GPRC5B controls macrophage function by facilitating prostaglandin E receptor 2 signaling," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56713-0
    DOI: 10.1038/s41467-025-56713-0
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    References listed on IDEAS

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    1. Tomi Lazarov & Sergio Juarez-Carreño & Nehemiah Cox & Frederic Geissmann, 2023. "Publisher Correction: Physiology and diseases of tissue-resident macrophages," Nature, Nature, vol. 619(7970), pages 51-51, July.
    2. H. Kaur & J. Carvalho & M. Looso & P. Singh & R. Chennupati & J. Preussner & S. Günther & J. Albarrán-Juárez & D. Tischner & S. Classen & S. Offermanns & N. Wettschureck, 2017. "Single-cell profiling reveals heterogeneity and functional patterning of GPCR expression in the vascular system," Nature Communications, Nature, vol. 8(1), pages 1-15, August.
    3. Calum C. Bain & Catherine A. Hawley & Hannah Garner & Charlotte L. Scott & Anika Schridde & Nicholas J. Steers & Matthias Mack & Anagha Joshi & Martin Guilliams & Allan Mc I. Mowat & Frederic Geissman, 2016. "Long-lived self-renewing bone marrow-derived macrophages displace embryo-derived cells to inhabit adult serous cavities," Nature Communications, Nature, vol. 7(1), pages 1-14, September.
    4. Tomi Lazarov & Sergio Juarez-Carreño & Nehemiah Cox & Frederic Geissmann, 2023. "Physiology and diseases of tissue-resident macrophages," Nature, Nature, vol. 618(7966), pages 698-707, June.
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