Kwon Jeonghyeon, Kawase Haruya, Mattonet Kenny, Guenther Stefan, Hahnefeld Lisa, Shamsara Jamal, Heering Jan, Kurz Michael, Kirchhofer Sina, Krasel Cornelius, Ulrich Michaela, Persechino Margherita, Murthy Sripriya, Orlandi Cesare, Sadik Christian D, Geisslinger Gerd, Bünemann Moritz, Kolb Peter, Offermanns Stefan, Wettschureck Nina
Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Imaging Platform, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Nat Commun. 2025 Feb 7;16(1):1448. doi: 10.1038/s41467-025-56713-0.
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.
巨噬细胞表达众多调节黏附、迁移和激活的G蛋白偶联受体（GPCR），但孤儿受体GPRC5B在巨噬细胞中的功能尚不清楚。来自髓系特异性GPRC5B缺陷小鼠的驻留腹膜巨噬细胞和骨髓来源巨噬细胞均表现出迁移和吞噬作用增强，从而在腹膜炎模型中改善细菌清除。在其他模型如心肌梗死中，髓系细胞募集增加具有不利影响。从机制上讲，我们发现GPRC5B与前列腺素受体家族的GPCR发生物理相互作用，导致通过前列腺素E受体2（EP2）的信号增强。在GPRC5B缺陷的巨噬细胞中，EP2介导的抗炎作用减弱，导致活性过高。通过计算机模拟和对接，我们确定了可能介导GPRC5B/EP2二聚化的残基，并表明它们的突变导致GPRC5B介导的EP2信号促进作用丧失。最后，我们证明模拟相互作用序列的诱饵肽能够减少GPRC5B介导的巨噬细胞中EP2诱导的cAMP信号促进作用。
