Embelin and its derivatives unravel the signaling, proinflammatory and antiatherogenic properties of GPR84 receptor

Gaidarov, Ibragim; Anthony, Todd L.; Gatlin, Joel; Chen, Xiaohua; Mills, David K.; Solomon, Michelle; Han, Sangdon; Semple, Graeme; Unett, David J.

doi:10.1016/j.phrs.2018.02.021

Cited by 43 publications

(92 citation statements)

References 39 publications

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“…Activation of both, HCA 3 and GPR84, resulted in phosphorylation of extracellular-signal regulated kinase (ERK) ( Figure S6A, Table S2). We did not observe calcium signals upon stimulation of either receptor ( Figure S6B) which partially contrasts previous findings [42,43]. However, the previously reported calcium signals in HCA 3 -transfected CHO-K1 cells have been reported at very high agonist concentrations, i.e.…”

Section: And Gpr84contrasting

confidence: 97%

“…100 μM of the synthetic agonist 1-isopropylbenzotriazole-5-carboxylic acid (IPBT5CA) [42], which has been reported to activate HCA 3 with an EC 50 value of 0.4 μM [44]. Additionally, Gaidarov et al showed that GPR84 activation evoked calcium responses only in human macrophages but not in transfected HEK293 cells which is in line with our findings [43].…”

Section: And Gpr84supporting

confidence: 91%

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

et al. 2020

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Background: Medium-chain fatty acids and their 3-hydroxy derivatives are metabolites endogenously produced in humans, food-derived or originating from bacteria. They activate G protein-coupled receptors, including GPR84 and HCA 3 , which regulate metabolism and immune functions. Although both receptors are coupled to G i proteins, share at least one agonist and show overlapping tissue expression, GPR84 exerts pro-inflammatory effects whereas HCA 3 is involved in anti-inflammatory responses. Here, we analyzed signaling kinetics of both HCA 3 and GPR84, to unravel signal transduction components that may explain their physiological differences. Methods: To study the signaling kinetics and components involved in signal transduction of both receptors we applied the label-free dynamic mass redistribution technology in combination with classical cAMP, ERK signaling and β-arrestin-2 recruitment assays. For phenotypical analyses, we used spheroid cell culture models. Results: We present strong evidence for a natural biased signaling of structurally highly similar agonists at HCA 3 and GPR84. We show that HCA 3 signaling and trafficking depends on dynamin-2 function. Activation of HCA 3 by 3hydroxyoctanoic acid but not 3-hydroxydecanoic acid leads to β-arrestin-2 recruitment, which is relevant for cellcell adhesion. GPR84 stimulation with 3-hydroxydecanoic acid causes a sustained ERK activation but activation of GPR84 is not followed by β-arrestin-2 recruitment. Conclusions: In summary, our results highlight that biased agonism is a physiological property of HCA 3 and GPR84 with relevance for innate immune functions potentially to differentiate between endogenous, non-pathogenic compounds and compounds originating from e.g. pathogenic bacteria.

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Section: And Gpr84contrasting

confidence: 97%

Section: And Gpr84supporting

confidence: 91%

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

et al. 2020

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“…In the continuing debate over the true physiological agonist(s) for the GPR84 receptor, researchers are placing increased reliance on chemical tool compounds to explore the role of GPR84 signaling in leukocyte biology ( 37 ). In this study, we chose to use the synthetic agonist 6-OAU rather than two other GPR84 synthetic agonists embelin ( 38 , 39 ) and DIM ( 12 , 15 ). This was because 6-OAU is so far, the most specific GPR84 agonist.…”

Section: Discussionmentioning

confidence: 99%

“…This was because 6-OAU is so far, the most specific GPR84 agonist. Embelin has been reported to potently inhibit the X-linked inhibitor of apoptosis protein in cancer cells ( 40 – 42 ) and has been shown to bind the Adenosine A3 receptor and CXCR2 ( 38 ). Diindolylmethane 2 (DIM) is an agonist at the cannabinoid receptor 2 (CB2) in macrophages ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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.

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“…After lysis of red blood cells by Pharmlyse (BD Biosciences, San Jose, CA, USA), 1 × 10 6 cells in RPMI-1640 were placed in the upper compartment of the 5-µm transwell migration chamber [19]. Migration was analyzed towards stimulation with a 3-µM embelin, a surrogate GPR84 agonist [20], or a 100-µM myristic acid (an MCFA) dissolved in combination with bovine serum albumin (BSA) in the lower compartment. The chemotactic cytokines, 5 nM CCL2 or 1 nM CXCL1, were used as positive controls for monocyte or neutrophil migration, respectively.…”

Section: Chemotaxis Assays For Murine Bone-marrow Monocytes and Neutrmentioning

confidence: 99%

The Medium-Chain Fatty Acid Receptor GPR84 Mediates Myeloid Cell Infiltration Promoting Steatohepatitis and Fibrosis

Puengel

Vos

Hundertmark

et al. 2020

JCM

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Medium-chain fatty acids (MCFAs) have been associated with anti-steatotic effects in hepatocytes. Expression of the MCFA receptor GPR84 (G protein-coupled receptor 84) is induced in immune cells under inflammatory conditions and can promote fibrogenesis. We aimed at deciphering the role of GPR84 in the pathogenesis of non-alcoholic steatohepatitis (NASH), exploring its potential as a therapeutic target. GPR84 expression is upregulated in liver from patients with non-alcoholic fatty liver disease (NAFLD), correlating with the histological degree of inflammation and fibrosis. In mouse and human, activated monocytes and neutrophils upregulate GPR84 expression. Chemotaxis of these myeloid cells by GPR84 stimulation is inhibited by two novel, small molecule GPR84 antagonists. Upon acute liver injury in mice, treatment with GPR84 antagonists significantly reduced the hepatic recruitment of neutrophils, monocytes, and monocyte-derived macrophages (MoMF). We, therefore, evaluated the therapeutic inhibition of GPR84 by these two novel antagonists in comparison to selonsertib, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, in three NASH mouse models. Pharmacological inhibition of GPR84 significantly reduced macrophage accumulation and ameliorated inflammation and fibrosis, to an extent similar to selonsertib. In conclusion, our findings support that GPR84 mediates myeloid cell infiltration in liver injury and is a promising therapeutic target in steatohepatitis and fibrosis.

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Embelin and its derivatives unravel the signaling, proinflammatory and antiatherogenic properties of GPR84 receptor

Cited by 43 publications

References 39 publications

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

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

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

The Medium-Chain Fatty Acid Receptor GPR84 Mediates Myeloid Cell Infiltration Promoting Steatohepatitis and Fibrosis

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