Agonists for G-protein-coupled receptor 84 (GPR84) alter cellular morphology and motility but do not induce pro-inflammatory responses in microglia

• Published in: Journal of neuroinflammation Vol. 14; no. 1; p. 198
• Main Authors: Wei, Li, Tokizane, Kyohei, Konishi, Hiroyuki, Yu, Hua-Rong, Kiyama, Hiroshi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 03.10.2017; BioMed Central; BMC
• Subjects: Animals; Animals, Newborn; Benzoquinones - pharmacology; Cell Movement - drug effects; Cells, Cultured; Central nervous system; Cerebral Cortex - cytology; Chemokines; Cyclic AMP - metabolism; Cytokines - genetics; Cytokines - metabolism; Decanoic Acids - pharmacology; Development and progression; Fatty acid; Fatty acids; Forskolin; G protein-coupled receptors; G-protein-coupled receptor 84; Gene Deletion; Genes; Genetic aspects; Inflammation; Laboratory animals; Ligands; Macrophages; Macrophages - drug effects; Membrane proteins; Membrane ruffling; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Microglia; Microglia - drug effects; Microglia - immunology; Microglia morphology; Microglia motility; Morphology; Motility; mRNA; Neuralgia; Neuronal-glial interactions; Neurons; Nitric Oxide Synthase Type II - metabolism; Nonsense mutation; Pain; Pertussis; Pertussis toxin; Pertussis Toxin - pharmacology; Physiological aspects; Pro-inflammatory response; Proteins; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Rodents; Signal transduction; Signal Transduction - drug effects; Tumor necrosis factor-TNF; Uracil - pharmacology; China; Microglia morphology; Pro-inflammatory response; Fatty acid; Microglia motility; G-protein-coupled receptor 84
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-017-0970-y

Several G-protein-coupled receptors (GPCRs) have been shown to be important signaling mediators between neurons and glia. In our previous screening for identification of nerve injury-associated GPCRs, G-protein-coupled receptor 84 (GPR84) mRNA showed the highest up-regulation by microglia after nerve injury. GPR84 is a pro-inflammatory receptor of macrophages in a neuropathic pain mouse model, yet its function in resident microglia in the central nervous system is poorly understood. We used endogenous, natural, and surrogate agonists for GPR84 (capric acid, embelin, and 6-OAU, respectively) and examined their effect on mouse primary cultured microglia in vitro. 6-n-Octylaminouracil (6-OAU), embelin, and capric acid rapidly induced membrane ruffling and motility in cultured microglia obtained from C57BL/6 mice, although these agonists failed to promote microglial pro-inflammatory cytokine expression. Concomitantly, 6-OAU suppressed forskolin-induced increase of cAMP in cultured microglia. Pertussis toxin, an inhibitor of Gi-coupled signaling, completely suppressed 6-OAU-induced microglial membrane ruffling and motility. In contrast, no 6-OAU-induced microglial membrane ruffling and motility was observed in microglia from DBA/2 mice, a mouse strain that does not express functional GPR84 protein due to endogenous nonsense mutation of the GPR84 gene. GPR84 mediated signaling causes microglial motility and membrane ruffling but does not promote pro-inflammatory responses. As GPR84 is a known receptor for medium-chain fatty acids, those released from damaged brain cells may be involved in the enhancement of microglial motility through GPR84 after neuronal injury.