Department of Rheumatology and Inflammation Research, Sahlgrenska, Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Oral Microbiology and Immunology, Institute of Odontology, Sahlgrenska Academy, University of Gothenburg, Sweden.
Biochim Biophys Acta Mol Cell Res. 2018 May;1865(5):695-708. doi: 10.1016/j.bbamcr.2018.02.008. Epub 2018 Feb 22.
GPR84 is a recently de-orphanized member of the G-protein coupled receptor (GPCR) family recognizing medium chain fatty acids, and has been suggested to play important roles in inflammation. Due to the lack of potent and selective GPR84 ligands, the basic knowledge related to GPR84 functions is very limited. In this study, we have characterized the GPR84 activation profile and regulation mechanism in human phagocytes, using two recently developed small molecules that specifically target GPR84 agonistically (ZQ16) and antagonistically (GLPG1205), respectively. Compared to our earlier characterization of the short chain fatty acid receptor FFA2R which is functionally expressed in neutrophils but not in monocytes, GPR84 is expressed in both cell types and in monocyte-derived macrophages. In neutrophils, the GPR84 agonist had an activation profile very similar to that of FFA2R. The GPR84-mediated superoxide release was low in naïve cells, but the response could be significantly primed by TNFα and by the actin cytoskeleton disrupting agent Latrunculin A. Similar to that of FFA2R, a desensitization mechanism bypassing the actin cytoskeleton was utilized by GPR84. All ZQ16-mediated cellular responses were sensitive to GLPG1205, confirming the GPR84-dependency. Finally, our data of in vivo transmigrated tissue neutrophils indicate that both GPR84 and FFA2R are involved in neutrophil recruitment processes in vivo. In summary, we show functional similarities but also some important differences between GPR84 and FFA2R in human phagocytes, thus providing some mechanistic insights into GPR84 regulation in blood neutrophils and cells recruited to an aseptic inflammatory site in vivo.
GPR84 是一种最近被重新鉴定的 G 蛋白偶联受体（GPCR）家族成员，能够识别中链脂肪酸，并被认为在炎症中发挥重要作用。由于缺乏有效的、选择性的 GPR84 配体，因此与 GPR84 功能相关的基础知识非常有限。在这项研究中，我们使用两种最近开发的分别特异性靶向 GPR84 激动剂（ZQ16）和拮抗剂（GLPG1205）的小分子，对人吞噬细胞中的 GPR84 激活谱和调节机制进行了表征。与我们之前对功能性表达于中性粒细胞而非单核细胞的短链脂肪酸受体 FFA2R 的表征相比，GPR84 在这两种细胞类型以及单核细胞衍生的巨噬细胞中均有表达。在中性粒细胞中，GPR84 激动剂的激活谱与 FFA2R 非常相似。在初始细胞中，GPR84 介导的超氧化物释放水平较低，但该反应可以被 TNFα 和肌动蛋白细胞骨架破坏剂拉曲库铵显著引发。与 FFA2R 相似，GPR84 利用一种绕过肌动蛋白细胞骨架的脱敏机制。所有由 ZQ16 介导的细胞反应均对 GLPG1205 敏感，证实了 GPR84 的依赖性。最后，我们体内迁移组织中性粒细胞的数据表明，GPR84 和 FFA2R 均参与体内中性粒细胞的募集过程。总之，我们在人吞噬细胞中显示了 GPR84 和 FFA2R 之间的功能相似性，但也存在一些重要差异，从而为体内血液中性粒细胞和招募到无菌炎症部位的细胞中 GPR84 的调节提供了一些机制见解。
