Activation of the immune-metabolic receptor GPR84 enhances inflammation and phagocytosis in macrophages

GPR84is a member of the metabolic G protein-coupled receptor family, and its expression has been described predominantly in immune cells. GPR84activation is involved in the inflammatory response but the mechanisms by which it modulates inflammation have been incompletely described. In this study, we investigated GPR84expression, activation and function in macrophages to establish the role of the receptor during the inflammatory response. We observed that GPR84expression in murine tissues is increased by endotoxemia, hyperglycemia and hypercholesterolemia. Ex vivo studies revealed that GPR84mRNA 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 oxidised LDL increased GPR84expression in macrophages. Activation of the GPR84receptor with a selective agonist, 6-(octylamino) pyrimidine-2,4(1H,3H)-dione (6-n-octylaminouracil, 6-OAU), enhanced the expression of p-AKT, p-ERK and p65 nuclear translocation under inflammatory conditions and elevated the expression levels of the inflammatory mediators TNFα, IL-6, IL-12B, CCL2, CCL5and CXCL1. In addition, GPR84activation 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 GPR84antagonist. Collectively, our results reveal that GPR84functions as an enhancer of inflammatory signalling in macrophages once inflammation is established. Therefore, molecules that antagonise the GPR84receptor may be potential therapeutic tools in inflammatory and metabolic diseases.