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

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Macrophages utilize numerous G protein-coupled receptors (GPCRs) to control critical functions like adhesion, migration, and activation.
• The specific role of the orphan receptor GPRC5B within macrophage biology remains largely uncharacterized.

Purpose of the Study:

• To elucidate the function of G protein-coupled receptor C5B (GPRC5B) in macrophages.
• To investigate the molecular mechanisms by which GPRC5B influences macrophage behavior and signaling pathways.

Main Methods:

• Generation and analysis of myeloid-specific GPRC5B-deficient mice.
• Assessment of macrophage migration, phagocytosis, and bacterial clearance in vivo.
• Co-immunoprecipitation and in silico modeling to identify GPRC5B interactions and signaling pathways.
• Functional assays using decoy peptides to disrupt GPRC5B-mediated signaling.

Main Results:

• Macrophages lacking GPRC5B exhibit heightened migration and phagocytic activity, leading to improved bacterial clearance in peritonitis models.
• GPRC5B deficiency results in diminished anti-inflammatory effects mediated by the prostaglandin E receptor 2 (EP2), causing macrophage hyperactivity.
• GPRC5B physically interacts with prostanoid receptors, specifically enhancing signaling through EP2.
• In silico analysis identified key residues for GPRC5B/EP2 dimerization, and mutations disrupted this interaction and GPRC5B's facilitation of EP2 signaling.
• Decoy peptides targeting the GPRC5B interaction site reduced GPRC5B-mediated facilitation of EP2-induced cAMP signaling in macrophages.

Conclusions:

• GPRC5B plays a crucial role in modulating macrophage inflammatory responses and phagocytic functions through interaction with EP2.
• While GPRC5B deficiency enhances bacterial clearance, it may have detrimental consequences in other inflammatory conditions due to altered myeloid cell recruitment and function.
• Targeting the GPRC5B-EP2 interaction presents a potential therapeutic strategy for modulating macrophage-driven inflammation.