The Role of Metabolite-Sensing G Protein-Coupled Receptors in Inflammation and Metabolic Disease

Recio, Carlota; Lucy, Daniel; Iqbal, Asif; Valaris, Sophia; Wynne, Graham M.; Russell, Angela J.; Choudhury, Robin P.; O’Callaghan, Chris; Monaco, Claudia; Greaves, David R.

doi:10.1089/ars.2017.7168

Cited by 13 publications

(13 citation statements)

References 193 publications

(179 reference statements)

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“…The concept of immunometabolism was first described in 2011, and it has emerged as a new field of scientific study ( 1 ). It highlights 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 ).…”

Section: Introductionmentioning

confidence: 99%

“…Within the G protein-coupled receptor (GPCR) superfamily, a subset of metabolite-sensing GPCRs has been shown to actively participate in inflammation during metabolic disease. They have been reported to respond to intermediates of energy metabolism including free-fatty acids, lactate, succinate, and ketone bodies, among others ( 3 , 7 ). GPCRs are seven transmembrane domain receptors that couple to heterotrimeric G proteins (Gαi, Gαs, Gαq, Gα 12/13 ) and/or β-arrestins.…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, they regulate the downstream intracellular signaling of kinase cascades, such as ERK/MAPK, JNK, p38, and Akt/PI3K. These pathways are central to the control of cell proliferation, differentiation, survival, migration, and other essential biological functions ( 3 , 8 , 9 ).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…GPR84 agonists also increase cholesterol efflux and are reported to be protective in atherosclerosis [ 63 ]. In addition, GPR84 receptor agonists increase inflammatory mediator levels, bacterial adhesion, and phagocytosis in macrophages [ 64 ].…”

Section: Lipid Metabolitesmentioning

confidence: 99%

Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases

Strassheim

Sullivan

Irwin

et al. 2021

Cells

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G protein-coupled receptors (GPCRs) have originally been described as a family of receptors activated by hormones, neurotransmitters, and other mediators. However, in recent years GPCRs have shown to bind endogenous metabolites, which serve functions other than as signaling mediators. These receptors respond to fatty acids, mono- and disaccharides, amino acids, or various intermediates and products of metabolism, including ketone bodies, lactate, succinate, or bile acids. Given that many of these metabolic processes are dysregulated under pathological conditions, including diabetes, dyslipidemia, and obesity, receptors of endogenous metabolites have also been recognized as potential drug targets to prevent and/or treat metabolic and cardiovascular diseases. This review describes G protein-coupled receptors activated by endogenous metabolites and summarizes their physiological, pathophysiological, and potential pharmacological roles.

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“…Classification into different families is based on sequence homology and to the types of ligands they can bind. Some GPCRs have been identified as important regulators of inflammation; both exacerbating inflammation and promoting its resolution [2]. Notably, several GPCRs have been shown to play a role in myometrial activation.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of GPR91 Reduces Inflammatory Mediators Involved in Active Labor in Myometrium

Lim

Lappas

2020

Mediators of Inflammation

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Problem. Some G-protein-coupled receptors (GPCRs) are regulators of inflammation, yet the role of the GPRC, GPR91, is unknown in human myometrium during the processes of human labor and delivery, a major inflammatory event. Method of Study. GPR91 mRNA expression was assessed using RT-qPCR in myometrium obtained from women at term Caesarean section in the absence of labor and during active spontaneous labor and in a mouse model of inflammation-induced preterm labor. Human primary myometrial cells were used to determine the effect of proinflammatory mediators on GPR91 and the effect of GPR91 siRNA on prolabor mediators. Statistical significance was ascribed to a P<0.05. Results. GPR91 mRNA expression was significantly higher in myometrium from women during term spontaneous labor compared to no labor. Likewise, in mice, GPR91 mRNA expression was significantly upregulated in myometrium during inflammation-induced preterm labor compared to preterm no labor. In myometrial cells, IL1B and TNF significantly increased GPR91 mRNA expression. Knockdown of GPR91 by siRNA in myometrial cells significantly suppressed the secretion and/or expression of IL1B- and TNF-induced proinflammatory cytokines (GM-CSF, IL1A, IL1B, and IL6) and chemokines (CXCL8 and CCL2), myometrial contractility (expression of the contraction-associated proteins PTGFR and CX43, secretion of the uterotonic PGF2α, and in situ collagen gel contraction), and the transcription factor NF-κB. Conclusion. Our findings demonstrate that GPR91 is involved in the genesis of proinflammatory and prolabor mediators induced by IL1B or TNF and collectively suggest that GPR91 may contribute to augmentation of the labor processes.

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The Role of Metabolite-Sensing G Protein-Coupled Receptors in Inflammation and Metabolic Disease

Cited by 13 publications

References 193 publications

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

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

Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases

Inhibition of GPR91 Reduces Inflammatory Mediators Involved in Active Labor in Myometrium

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