Three classes of ligands each bind to distinct sites on the orphan G protein-coupled receptor GPR84

Mahmud, Zobaer Al; Jenkins, Laura; Ulven, Trond; Labéguère, Frédéric; Gosmini, Romain; Vos, Steve De; Hudson, Brian D.; Tikhonova, Irina G.; Milligan, Graeme

doi:10.1038/s41598-017-18159-3

Cited by 43 publications

(170 citation statements)

References 49 publications

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“…When comparing results from Bukowski et al [25] only 7 genes are shared with our study. All these genes may be in one way or another related to PTB: CCRL2 and CXCL2 belong to inflammatory pathways [55,56], GPR84 is a receptor of fatty acids also related to inflammation [57]. BCL2A1 and CHI3L1 were recently associated with chorioamnionitis in monkey and human [58], SLC16A10 is up-regulated in the mid-gestational placenta [59] and SAMSN1 is a poorly characterized gene that may be involved in differentiation of lymphocytes B [60].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of fetal membranes reveals pathways involved in preterm birth

Pereyra

Bertoni

Sosa

et al. 2018

Preprint

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15 16 Short title: Transcriptomic analysis of severe preterm birth 17 Key words: RNA-seq, preterm birth, gestational age, biomarkers 18 2 19Abstract 20 Preterm birth (PTB), defined as infant delivery before 37 weeks of completed gestation, results of 21 the interaction of both genetic and environmental components and constitutes a complex 22 multifactorial syndrome. Transcriptome analysis of PTB has proved challenging because of the 23 multiple causes of PTB and the numerous maternal and fetal gestational tissues that must interact 24 to facilitate parturition. A common pathway of labor and PTB may be the activation of fetal 25 membranes. In this work, chorioamnion membranes from severe preterm and term fetus were 26 analyzed using RNA sequencing. A total of 270 genes were differentially expressed (DE): 252 27 were up-regulated and 18 were down-regulated in the severe preterm compared to the term births. 28 We found great gene expression homogeneity in the control samples, and not in severe preterm 29 samples. In this work, we identified up-regulated pathways that were previously suggested as 30 leading to PTB like immunological and inflammatory paths. New pathways that were not 31 identified in preterm like the hemopoietic path appeared up-regulated in preterm membranes. A 32 group of 18 down-regulated genes discriminates between term and severe preterm cases. These 33 genes potentially characterize a severe preterm transcriptome pattern and therefore are candidate 34 genes for understanding the syndrome. Some of the down-regulated genes are involved in the 35 nervous system, morphogenesis (WNT-1, DLX5, PAPPA2) and ion channel complexes (KCNJ16, 36 KCNB1), making them good candidates as biomarkers of PTB.37 The identification of this DE gene pattern may help to develop a multi-gene disease classifier.38 These markers were generated in an admixtured South American population where PTB has a high 39 incidence. Since genetic background may impact differentially in different populations it is 40 mandatory to include populations like South American and African ones that are usually excluded 3 41 from high throughput approaches. These classifiers should be compared to those in other 42 populations to get a global landscape of PTB. 43 44 Introduction 45 Preterm birth (PTB), defined as the delivery of an infant before 37 weeks of completed gestation, 46 is a worldwide health problem and remains the leading cause of global perinatal morbidity and 47 mortality [1][2][3]. PTB is a complex, multifactorial syndrome comprised of multiple clinical 48 subtypes that can be defined as either 'spontaneous' or 'medically indicated' [4,5]. 70 % of PTB 49 cases are idiopathic; 5 % are due to the spontaneous onset of labor (sPTB) and the remaining 25 50 % are consequence of the preterm premature rupture of membranes (PPROM) [5,6]. PTB has also 51 been stratified according to gestational age (GA); neonates born between 24 and 33 weeks (severe 52 PTB) are at higher risk of death, and diseases later in life, than moderate PTB (GA betwee...

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Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of fetal membranes reveals pathways involved in preterm birth

Pereyra

Bertoni

Sosa

et al. 2018

Preprint

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“…Several studies have characterized GPR84 as a medium chain fatty acid (MCFA) receptor, with capric acid (a 10-carbon chain fatty acid) being the most potent ligand ( 11 ). However, GPR84 is not officially a “deorphanized” receptor, yet, as there is not a consensus that MCFAs are the major endogenous ligands that activate GPR84 ( 12 ). Numerous studies have focused their attention on developing new GPR84 agonist compounds with improved potency, selectivity, and specificity.…”

Section: Introductionmentioning

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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“…Background G protein-coupled receptors (GPCRs) activated by metabolites originating from diet, host-and microbiota metabolism gain more and more attention due to their role as regulators of the host (patho)-physiological state [1][2][3][4]. Medium-chain fatty acids (MCFAs), which are saturated fatty acids with 8 to 12 carbons, and their 3hydroxy derivatives are metabolites acting as agonists at the hydroxycarboxylic acid receptor 3 (HCA 3 ) and GPR84 [5][6][7][8][9]. MCFAs originate from medium-chain triacylglycerols present in dairy products and reach plasma levels up to 18 μM, which are further increased under medium-chain triacylglycerol diet [10][11][12][13][14][15][16][17].…”

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confidence: 99%

“…3HDec is also an agonist at GPR84 [7]. 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].…”

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confidence: 99%

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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Three classes of ligands each bind to distinct sites on the orphan G protein-coupled receptor GPR84

Cited by 43 publications

References 49 publications

Transcriptomic analysis of fetal membranes reveals pathways involved in preterm birth

Transcriptomic analysis of fetal membranes reveals pathways involved in preterm birth

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

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

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