A Biased Agonist at Immunometabolic Receptor GPR84 Causes Distinct Functional Effects in Macrophages
A Biased Agonist at Immunometabolic Receptor GPR84 Causes Distinct Functional Effects in Macrophages
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DOI：
10.1021/acschembio.9b00533
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发表时间：
2019-09-01
影响因子：
4
通讯作者：
Russell, Angela J.
中科院分区：
文献类型：
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作者：
Lucy, Daniel;Purvis, Gareth S. D.;Russell, Angela J.
GPR84 是一种孤儿 G 蛋白偶联受体，在免疫细胞上表达，与多种炎症性疾病有关。 GPR84 作为治疗靶点的验证受到可用化学工具范围狭窄以及随之而来的对 GPR84 病理生理学了解不足的阻碍。在这里，我们描述了 DL-175 的发现和表征，DL-175 是一种有效的、选择性的、结构新颖的 GPR84 激动剂，也是第一个在 GPR84 过表达细胞、原代鼠巨噬细胞和人 U937 细胞中显示出显着偏向信号传导的药物。通过将 DL-175 与报道的 GPR84 配体进行比较，我们首次表明，偏向的 GPR84 激动剂在诱导人骨髓细胞趋化性方面具有显着不同的能力，同时引起相似水平的吞噬作用增强。这项工作表明，GPR84 的偏向激动能够选择性激活免疫细胞中的功能反应，并为进一步研究提供高质量的化学探针。
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.