Activation of the Immune-Metabolic Receptor GPR84 Enhances Inflammation and Phagocytosis in Macrophages

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.

Natural biased signaling of hydroxycarboxylic acid receptor 3 and G protein-coupled receptor 84

“…As mentioned above, GPR84 functions as an enhancer of inflammatory signaling in macrophages once inflammation is established whereas a contrary role is suggested for HCA 3 [25,27]. Further, both receptors are coexpressed in different types of immune cells (Table S5), and share the agonist 3HDec.…”

“…Although the role of MCFAs (C10 -C14), specifically decanoic acid (C10), as endogenous agonists at GPR84 is disputed [24], recent work supports their relevance as major endogenous ligands [8,9]. Both, HCA 3 and GPR84, are G i protein-coupled receptors and expressed in immune cells, such as neutrophils, macrophages and monocytes [6,7,[25][26][27]. GPR84 promotes chemotaxis and proinflammatory cytokine release in leukocytes and macrophages [6,7,27].…”

“…Both, HCA 3 and GPR84, are G i protein-coupled receptors and expressed in immune cells, such as neutrophils, macrophages and monocytes [6,7,[25][26][27]. GPR84 promotes chemotaxis and proinflammatory cytokine release in leukocytes and macrophages [6,7,27]. Moreover, chemotaxis of neutrophils and monocytes upon HCA 3 activation has been reported [25,26].…”

SILAC-based quantitative proteomics reveals pleiotropic, phenotypic modulation in primary murine macrophages infected with the protozoan pathogenLeishmania donovani

“…Our data demonstrate that L. donovani promastigotes inhibit host cell immune functions by down-regulation of several macrophage proteins that participate in immunomodulation and innate immunity (Cd180/Q62192, r 1 =0.66, r 2 =0.76; Tlr13/Q6R5N8, r 1 =0.66, r 2 =0.5; Grn/P28798, r 1 =0.7, r 2 =0.62; Arrb2/Q91YI4, r 1 =0.61, r 2 =0.4; Gpr84/Q8CIM5, r 1 =0.64 and r 2 =1/∞; Hmox-1/P14901, r 1 =0.67, r 2 =0.39; Mpeg1/A1L314, r 1 =0.31, r 2 =0.4) ( Table 2 ). These results indicate that infection likely dampens the macrophage pro-inflammatory response given the observed down-modulation of (i) Tlr13, which acts via Myd88 and Traf6 leading to NF-κΒ activation [64], (ii) Granulin (Grn) a soluble cofactor for Tlr9 signaling [65], and (iii) the G-protein coupled receptor Grp84 known to be activated by medium-chain free fatty acids to enhance inflammation and phagocytosis in macrophages [66].…”

Development of a Bioinformatics Framework for Identification and Validation of Genomic Biomarkers and Key Immunopathology Processes and Controllers in Infectious and Non-infectious Severe Inflammatory Response Syndrome

“…GPR84 is a G protein-coupled receptor for medium-chain fatty acids (74). It is expressed in neutrophils, monocytes and macrophages (75,76) and can modulate pro-inflammatory TNFα mRNA expression in endotoxin-tolerant human monocytes when activated with its ligand decanoic acid (77). It is highly expressed on the surface of peripheral blood leukocytes and is responsible for IP3-Ca2+ signaling, mobilization of intracellular granules, chemotactic migration, as well as assembly of reactive oxygen species generating NADPH-oxidase.…”