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Extracellular Succinate Hyperpolarizes M2 Macrophages through SUCNR1/GPR91-Mediated Gq Signaling

ABSTRACT: Succinate functions both as a classical TCA cycle metabolite and as an extracellular metabolic stress signal sensed by the mainly Gi-coupled succinate receptor, SUCNR1. In the present study, we characterize and compare effects and signaling pathways activated by succinate and both classes of non-metabolite SUCNR1 agonists. By use of specific receptor and pathway inhibitors, rescue in G protein depleted cells and monitoring of receptor G protein activation by BRET we surprisingly identify Gq rather than Gi signaling, to be responsible for SUCNR1-mediated effects on basic transcriptional regulation. Importantly, in primary human M2 macrophages, where SUCNR1 is highly expressed, we demonstrate that physiological concentrations of extracellular succinate act through SUCNR1 activated Gq signaling to efficiently regulate transcription of immune function genes in a manner that hyperpolarizes their M2 versus M1 phenotype. Thus, sensing of stress-induced extracellular succinate by SUCNR1 is an important transcriptional regulator in human M2 macrophages through Gq signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE173611 | GEO | 2021/04/30

REPOSITORIES: GEO

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Extracellular Succinate Hyperpolarizes M2 Macrophages through SUCNR1/GPR91-Mediated Gq Signaling

Project description:Extracellular Succinate Hyperpolarizes M2 Macrophages through SUCNR1/GPR91-Mediated Gq Signaling

| PRJNA726262 | ENA

Effect of depletion of succinate receptor 1 (SUCNR1) on the gene expression of mouse adipose tissue

Project description:The concept of “signaling metabolites” in the control of metabolic homeostasis is gaining traction. The Krebs cycle substrate succinate, a pleiotropic metabolite that acts akin to hormones and cytokines through succinate receptor 1 (SUCNR1, also known as GPR91), is one example of this new class of metabolites. SUCNR1 has a broad expression and is highly abundant in white adipose tissue. It was a general assumption that SUCNR1 is functionally inactive in healthy tissues, and for many years, SUCNR1 was explored from an immune perspective, mainly in inflammatory-related conditions, particularly those associated with chronic hypersuccinemia. Recent studies, however, indicate that extracellular levels of succinate transiently increase in response to physiological changes such as exercise, cold exposure, or food ingestion. Succinate thus emerges as a reporter of both tissue stress and metabolism, raising the possibility of its involvement in additional metabolic functions as a hormone-like metabolite. Indeed, it is conceivable that "succinate sensing" by SUCNR1 may be part of the metabolite-sensing machinery that governs energy homeostasis. To better understand the effect of the adipocyte Sucnr1 deletion on adipose tissue, we selectively inactivated Sucnr1 in murine adipocytes and profiled the transcription state of epididymal white adipose tissue from adipocyte cell-specific Sucnr1 knockout mice (Ad-Sucnr1 KO) and control Sucnr1fl/fl mice.

2023-03-27 | GSE200749 | GEO

SUCNR1 signaling controls macrophage alternative activation

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SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes.

Project description:Obesity induces macrophages to drive inflammation in adipose tissue, a crucial step towards the development of type 2 diabetes. The tricarboxylic acid (TCA) cycle intermediate succinate is released from cells under metabolic stress and has recently emerged as a metabolic signal induced by proinflammatory stimuli. We therefore investigated whether succinate receptor 1 (SUCNR1) could play a role in the development of adipose tissue inflammation and type 2 diabetes. Succinate levels were determined in human plasma samples from individuals with type 2 diabetes and non-diabetic participants. Succinate release from adipose tissue explants was studied. Sucnr1 -/- and wild-type (WT) littermate mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 16 weeks. Serum metabolic variables, adipose tissue inflammation, macrophage migration and glucose tolerance were determined. We show that hypoxia and hyperglycaemia independently drive the release of succinate from mouse adipose tissue (17-fold and up to 18-fold, respectively) and that plasma levels of succinate were higher in participants with type 2 diabetes compared with non-diabetic individuals (+53%; p < 0.01). Sucnr1 -/- mice had significantly reduced numbers of macrophages (0.56 ± 0.07 vs 0.92 ± 0.15 F4/80 cells/adipocytes, p < 0.05) and crown-like structures (0.06 ± 0.02 vs 0.14 ± 0.02, CLS/adipocytes p < 0.01) in adipose tissue and significantly improved glucose tolerance (p < 0.001) compared with WT mice fed an HFD, despite similarly increased body weights. Consistently, macrophages from Sucnr1 -/- mice showed reduced chemotaxis towards medium collected from apoptotic and hypoxic adipocytes (-59%; p < 0.05). Our results reveal that activation of SUCNR1 in macrophages is important for both infiltration and inflammation of adipose tissue in obesity, and suggest that SUCNR1 is a promising therapeutic target in obesity-induced type 2 diabetes.

2017-04-07 | GSE64104 | GEO

Microarray experiment to characterise the signalling pathways downstream SUCNR1 activation in murine Neural Stem Cells (NSCs)

Project description:This experiment aimed at characterising the signalling pathways downstream SUCNR1 activation in murine Neural Stem Cells (NSCs). To this end, we profiled by microarray the gene expression changes induced by succinate stimulation in both wild type NSCs and GPR91-deficient NSCs.

2018-01-01 | E-MTAB-5586 | biostudies-arrayexpress

UCP1-dependent depletion of liver extracellular succinate antagonizes inflammatory pathogenesis

Project description:Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide and is intimately linked with obesity and type 2 diabetes. Liver inflammation is a hallmark of NAFLD and is thought to contribute to tissue fibrosis and disease pathogenesis. Uncoupling protein 1 (UCP1) is exclusively expressed in brown and beige adipocytes and has been extensively studied for its capacity to elevate thermogenesis and reverse obesity. Here we identify an endocrine pathway regulated by UCP1 that antagonizes liver inflammation and pathology, independent of effects on obesity. We show that, without UCP1, brown and beige fat exhibit a diminished capacity to clear succinate from the circulation. Moreover, UCP1KO mice exhibit elevated extracellular succinate in liver tissue that drives inflammation through ligation of its cognate receptor succinate receptor 1 (SUCNR1) in liver-resident stellate cell and macrophage populations. Conversely, increasing brown and beige adipocyte content in mice antagonizes SUCNR1-dependent inflammatory signaling in the liver. We show that this UCP1-succinate-SUCNR1 axis is necessary to regulate liver immune cell infiltration and pathology, and systemic glucose intolerance in an obesogenic environment. As such, the therapeutic utility of brown and beige adipocytes, and UCP1, extends beyond thermogenesis and may be leveraged to antagonize NAFLD and SUCNR1-dependent liver inflammation.

2022-02-17 | PXD024717 | Pride

SUCNR1 signaling controls macrophage alternative activation

Project description:SUCNR1 signaling controls macrophage alternative activation

| PRJNA491693 | ENA

The metabolite receptor SUCNR1 in oxidative stress-induced age-related macular degeneration

Project description:The metabolite receptor SUCNR1 in oxidative stress-induced age-related macular degeneration

| PRJNA587943 | ENA

Structural mechanism underlying primary and secondary coupling between GPCRs and the Gi/o family

Project description:G protein-coupled receptors (GPCRs) are the largest receptor superfamily that can propagate various extracellular stimulus into cells by coupling with heterotrimeric G proteins. G proteins are divided into four families, Gs, Gi/o, Gq/11 and G12/13, which are responsible for the transduction of discrete downstream signaling pathways. Interestingly, one receptor can couple to more than one G protein subtype with different coupling efficiency or kinetics; coupling with the highest efficiency and/or kinetics is known as ‘primary coupling’ whereas the one with lower efficiency and/or slower kinetics is known as ‘secondary coupling’. Due to its significance in human physiology, there has been a great effort to elucidate the precise mechanism of GPCR-G protein coupling, however, the complex nature of GPCR and G protein interaction raises more unanswered questions. Here, we utilized hydrogen/deuterium exchange mass spectrometry (HDX-MS) to understand the molecular mechanism underlying primary and secondary Gi/o coupling using muscarinic acetylcholine receptor type 2 (M2R) and β2-adrenergic receptor (β2AR) as the primary and secondary Gi/o-coupling receptors, respectively. Results showed the engagement of the distal C-terminus of Gi/o with the receptor differentiates primary and secondary Gi/o couplings. In addition, the interaction between the intracellular loop 2 (ICL2) of the receptor and Gi/o in primary Gi/o coupling is not as critical as in primary Gs coupling.

2020-07-02 | PXD019367 | Pride

The metabolite receptor SUCNR1 in oxidative stress-induced age-related macular degeneration

Project description:Murine RPE transcriptomes were generated from SUCNR1 WT and KO mice from both the treated and untreated groups (n=4). When comparing all groups to each other, no significant difference in gene expression was observed.

2020-01-31 | GSE139996 | GEO

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