Abstract
BackgroundSeveral 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.MethodsWe 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.Results6-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.ConclusionsGPR84 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.
Highlights
Several G-protein-coupled receptors (GPCRs) have been shown to be important signaling mediators between neurons and glia
G-proteincoupled receptor 84 (GPR84) does not alter pro-inflammatory responses of cultured microglia Previous studies have reported a pro-inflammatory role for GPR84 in macrophages [17, 18]
The present study demonstrates that GPR84 does not modulate pro-inflammatory responses in primary cultured microglia
Summary
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-proteincoupled 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. In our previous GPCR screening study, mRNA encoding G-protein-coupled receptor 84 (GPR84) showed highest up-regulation (increased by approximately 47-fold) in microglia after neuronal injury [3]. A 2-bp frame-shift deletion in the second exon of the GPR84 gene has been discovered in some classical inbred mouse strains This deletion generates a premature stop codon, resulting in a truncated protein that lacks transmembrane domains 4–7 [11]. Microglia responded to nerve injury with prominent upregulation of GPR84 mRNA in the neuropathic pain model [13], as well as our motor nerve injury model [3], in which circulating macrophages do not contribute to the microglial pool [14,15,16], and thereby conflicts with the conclusion that there is no functional consequence of GPR84 deficiency in microglia [13]
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