期刊
FRONTIERS IN IMMUNOLOGY
卷 9, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2018.01419
关键词
immunometabolism; inflammation; metabolic G protein-coupled receptors; GPR84; macrophages
类别
资金
- Novo Nordisk Foundation grant [NNF15CC0018346]
- British Heart Foundation grants [RG/15/10/23915]
- BHF Centre of Research Excellence [RE/13/1/30181]
- Diabetes UK grant [15/0005171]
- Wellcome Trust Veterinary Postdoctoral Fellowship [WT096398MA]
- Wellcome Trust Edward Penley Abraham Research Fund [RF 238]
- MRC [MR/R007977/1] Funding Source: UKRI
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [UM1OD023221] Funding Source: NIH RePORTER
GPR84 is a member of the metabolic G protein-coupled receptor family, and its expression has been described predominantly in immune cells. GPR84 activation is involved in the inflammatory response, but the mechanisms by which it modulates inflammation have been incompletely described. In this study, we investigated GPR84 expression, activation, and function in macrophages to establish the role of the receptor during the inflammatory response. We observed that GPR84 expression in murine tissues is increased by endotoxemia, hyperglycemia, and hypercholesterolemia. Ex vivo studies revealed that GPR84 mRNA expression is increased by LPS and other pro-inflammatory molecules in different murine and human macrophage populations. Likewise, high glucose concentrations and the presence of oxidized LDL increased GPR84 expression in macrophages. Activation of the GPR84 receptor with a selective agonist, 6-(octylamino) pyrimidine-2,4(1H, 3H)-dione (6-n-octylaminouracil, 6-OAU), enhanced the expression of phosphorylated Akt, p-ERK, and p65 nuclear translocation under inflammatory conditions and elevated the expression levels of the inflammatory mediators TNF alpha, IL-6, IL-12B, CCL2, CCL5, and CXCL1. In addition, GPR84 activation triggered increased bacterial adhesion and phagocytosis in macrophages. The enhanced inflammatory response mediated by 6-OAU was not observed in GPR84(-/-) cells nor in macrophages treated with a selective GPR84 antagonist. Collectively, our results reveal that GPR84 functions as an enhancer of inflammatory signaling in macrophages once inflammation is established. Therefore, molecules that antagonize the GPR84 receptor may be potential therapeutic tools in inflammatory and metabolic diseases.
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