Molecular Identification of a Novel Cellular Ligand of Gpr97/Adgrg3 and Functional Characterization of Gpr97-Ligand Interaction in Human Neutrophils

G protein-coupled receptor 97 (GPR97/ADGRG3) is a member of the adhesion G protein-coupled receptors (aGPCRs) that constitute the second largest GPCR sub-family in human. Murine Gpr97 was implicated in the fate decision of the follicular versus marginal zone B lymphocytes and the migration of lymphatic endothelial cells. By contrast, Gpr97 was dispensable for the metabolic syndrome in high-fat diet-induced obesity as well as for inflammation in OVA-induced asthmatic mice. Despite these functional analyses of murine Gpr97, little is known of the role of human GPR97 receptor. In the present project, we first generated a human GPR97-specific mAb for its expressional and functional characterization in the immune system. We find that GPR97 is distinctively expressed in polymorphonuclear granulocytes (PMNs), but not in other immune cell types. GPR97 expression is further up-regulated upon PMN activation. Receptor ligation by the anti-GPR97 mAb potentiates the production of reactive oxygen species induced by f-MLF, suggesting a role for GPR97 in modulating innate immune responses. Being a typical aGPCR, we hypothesize that GPR97 might function via the interaction with putative GPR97-interacting partners (ligands). Indeed, we are able to detect a highly GPR97-specific cellular ligand on a subpopulation of PMNs using the chimeric GPR97-mFc protein probe. Herein, we aim to further explore the regulation and function of GPR97 receptor and the putative GPR97-ligand in human PMNs. Specifically we propose to examine the regulation of GPR97 expression during PMN activation and in various disease states. Next, we will investigate GPR97-mediated activation and signaling pathways involved in modulating PMN effector functions. Finally, the molecular identity of the putative GPR97-ligand and the functional outcome of GPR97 receptor-ligand interaction will be pursued. Results of this study are expected to provide critical insights into how the activation and function of PMNs are regulated by GPR97 receptor-ligand interaction.

Project ID:PC10901-1638
External Project ID:MOST107-2320-B182-006-MY3