A Biased Agonist at Immunometabolic Receptor GPR84 Causes Distinct Functional Effects in Macrophages

• DOI: 10.1021/acschembio.9b00533
• Publication Date: 2019-08-29T16:26:30Z
• Authors: Daniel Lucy; Gareth S. D. Purvis; Lynda Zeboudj; Maria Chatzopoulou; Carlota Recio; Carole J. R. Bata...; Graham M. Wynne; David R. Greaves; Angela J. Russell
• Keywords: Cell signaling; Pyridines; 320710 Inmunopatología; Immunology; Quantitative Structure-Activity Relationship; CHO Cells; Assays; Receptors, G-Protein-Coupled; Cyclic N-Oxides; Mice; 03 medical and health sciences; Cricetulus; Phagocytosis; 3207 Patología; Cell Line, Tumor; Receptors; Animals; Humans; 0303 health sciences; Chemotactic Factors; Molecular Structure; Macrophages; 2407 Biología celular; 3. Good health; Agonists; Signal Transduction

GPR84 is an orphan G-protein-coupled receptor that is expressed on immune cells and implicated in several inflammatory diseases. The validation of GPR84 as a therapeutic target is hindered by the narrow range of available chemical tools and consequent poor understanding of GPR84 pathophysiology. Here we describe the discovery and characterization of DL-175, a potent, selective, and structurally novel GPR84 agonist and the first to display significantly biased signaling across GPR84-overexpressing cells, primary murine macrophages, and human U937 cells. By comparing DL-175 with reported GPR84 ligands, we show for the first time that biased GPR84 agonists have markedly different abilities to induce chemotaxis in human myeloid cells, while causing similar levels of phagocytosis enhancement. This work demonstrates that biased agonism at GPR84 enables the selective activation of functional responses in immune cells and delivers a high-quality chemical probe for further investigation.