Abstract
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 TNFα, 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.
Highlights
The concept of immunometabolism was first described in 2011, and it has emerged as a new field of scientific study [1]
We found that the synthetic GPR84 agonist 6-n-octylaminouracil 4 (6-OAU) upregulated the Akt, ERK, and the nuclear factor κB (NFκB) signaling pathways, amplified the expression of inflammatory mediators, and increased bacterial adhesion and phagocytosis in murine pro-inflammatory macrophages
We show that the GPR84 receptor is upregulated in murine macrophages under inflammatory conditions in vitro, in Human Monocyte-Derived Macrophages (hMDMs) ex vivo, and in mouse models of endotoxemia and immuno-metabolic stress in vivo
Summary
The concept of immunometabolism was first described in 2011, and it has emerged as a new field of scientific study [1] It high lights the regulatory interactions between innate and adaptive immunity and metabolism and provides new insights into disease mechanisms with the potential to identify new targets for therapeutic intervention [2, 3]. Macrophages can be of bone marrow origin or can be tissue-resident macrophages derived from fetal monocytes [5] Their major functions include phagocytosis, antigen presentation, and immunomodulation through the production of cytokines, chemokines, and other inflammatory mediators. They are critical cells in the initiation, maintenance, and resolution of inflammation and are interesting to target in inflammatory disease [6]
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