-
Molecular Cell Jan 2020Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived...
Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.
Topics: A549 Cells; Animals; Cell Line, Tumor; Cell Movement; HT29 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms; MCF-7 Cells; Macrophages; Mice, Inbred C57BL; Neoplasm Metastasis; PC-3 Cells; Receptors, G-Protein-Coupled; Signal Transduction; Succinic Acid; Tumor Microenvironment
PubMed: 31735641
DOI: 10.1016/j.molcel.2019.10.023 -
Cell Metabolism Aug 2022The tumor microenvironment (TME) is a unique metabolic niche that can inhibit T cell metabolism and cytotoxicity. To dissect the metabolic interplay between tumors and...
The tumor microenvironment (TME) is a unique metabolic niche that can inhibit T cell metabolism and cytotoxicity. To dissect the metabolic interplay between tumors and T cells, we establish an in vitro system that recapitulates the metabolic niche of the TME and allows us to define cell-specific metabolism. We identify tumor-derived lactate as an inhibitor of CD8 T cell cytotoxicity, revealing an unexpected metabolic shunt in the TCA cycle. Metabolically fit cytotoxic T cells shunt succinate out of the TCA cycle to promote autocrine signaling via the succinate receptor (SUCNR1). Cytotoxic T cells are reliant on pyruvate carboxylase (PC) to replenish TCA cycle intermediates. By contrast, lactate reduces PC-mediated anaplerosis. The inhibition of pyruvate dehydrogenase (PDH) is sufficient to restore PC activity, succinate secretion, and the activation of SUCNR1. These studies identify PDH as a potential drug target to allow CD8 T cells to retain cytotoxicity and overcome a lactate-enriched TME.
Topics: CD8-Positive T-Lymphocytes; Humans; Immunity; Lactic Acid; Neoplasms; Pyruvate Carboxylase; Pyruvic Acid; Succinic Acid; Tumor Microenvironment
PubMed: 35820416
DOI: 10.1016/j.cmet.2022.06.008 -
Cell Metabolism Jul 2016Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation accompanying inflammatory macrophage activation. During this process, endogenous metabolites...
Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the pro-inflammatory IL-1β-HIF-1α axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions by inhibiting succinate dehydrogenase-mediated oxidation of succinate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1(-/-) mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages.
Topics: Animals; Cell Respiration; Female; Inflammation; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice, Inbred C57BL; Mitochondria; Reactive Oxygen Species; Reperfusion Injury; Succinate Dehydrogenase; Succinates; Succinic Acid
PubMed: 27374498
DOI: 10.1016/j.cmet.2016.06.004 -
Gut Microbes 2023Succinate is a circulating metabolite, and the relationship between abnormal changes in the physiological concentration of succinate and inflammatory diseases caused by... (Review)
Review
Succinate is a circulating metabolite, and the relationship between abnormal changes in the physiological concentration of succinate and inflammatory diseases caused by the overreaction of certain immune cells has become a research focus. Recent investigations have shown that succinate produced by the gut microbiota has the potential to regulate host homeostasis and treat diseases such as inflammation. Gut microbes are important for maintaining intestinal homeostasis. Microbial metabolites serve as nutrients in energy metabolism, and act as signal molecules that stimulate host cell and organ function and affect the structural balance between symbiotic gut microorganisms. This review focuses on succinate as a metabolite of both host cells and gut microbes and its involvement in regulating the gut - immune tissue axis by activating intestinal mucosal cells, including macrophages, dendritic cells, and intestinal epithelial cells. We also examined its role as the mediator of microbiota - host crosstalk and its potential function in regulating intestinal microbiota homeostasis. This review explores feasible ways to moderate succinate levels and provides new insights into succinate as a potential target for microbial therapeutics for humans.
Topics: Humans; Gastrointestinal Microbiome; Host Microbial Interactions; Microbiota; Intestinal Mucosa; Succinic Acid; Succinates
PubMed: 36946592
DOI: 10.1080/19490976.2023.2190300 -
Cell Reports Dec 2022Neurotransmitters have been well documented to determine immune cell fates; however, whether and how γ-amino butyric acid (GABA) shapes the function of innate immune...
Neurotransmitters have been well documented to determine immune cell fates; however, whether and how γ-amino butyric acid (GABA) shapes the function of innate immune cells is still obscure. Here, we demonstrate that GABA orchestrates macrophage maturation and inflammation. GABA treatment during macrophage maturation inhibits interleukin (IL)-1β production from inflammatory macrophages. Mechanistically, GABA enhances succinate-flavin adenine dinucleotide (FAD)-lysine specific demethylase1 (LSD1) signaling to regulate histone demethylation of Bcl2l11 and Dusp2, reducing formation of the NLRP3-ASC-Caspase-1 complex. The GABA-succinate axis reduces succinylation of mitochondrial proteins to promote oxidative phosphorylation (OXPHOS). We also find that GABA alleviates lipopolysaccharides (LPS)-induced sepsis as well as high-fat-diet-induced obesity in mice. Our study shows that GABA regulates pro-inflammatory macrophage responses associated with metabolic reprogramming and protein succinylation, suggesting a strategy for treating macrophage-related inflammatory diseases.
Topics: Mice; Animals; Succinic Acid; Lysine; Mitochondrial Proteins; Macrophages; gamma-Aminobutyric Acid
PubMed: 36476877
DOI: 10.1016/j.celrep.2022.111770 -
Nutrients Dec 2018Succinate is a metabolic intermediate of the tricarboxylic acid (TCA) cycle within host cells. Succinate is also produced in large amounts during bacterial fermentation... (Review)
Review
Succinate is a metabolic intermediate of the tricarboxylic acid (TCA) cycle within host cells. Succinate is also produced in large amounts during bacterial fermentation of dietary fiber. Elevated succinate levels within the gut lumen have been reported in association with microbiome disturbances (dysbiosis), as well as in patients with inflammatory bowel disease (IBD) and animal models of intestinal inflammation. Recent studies indicate that succinate can activate immune cells via its specific surface receptor, succinate receptor 1(SUCNR1), and enhance inflammation. However, the role of succinate in inflammatory processes within the gut mucosal immune system is unclear. This review includes current literature on the association of succinate with intestinal inflammation and the potential role of succinate⁻SUCNR1 signaling in gut immune functions.
Topics: Animals; Bacteria; Dysbiosis; Gastrointestinal Microbiome; Humans; Immunity, Innate; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Receptors, G-Protein-Coupled; Signal Transduction; Succinic Acid
PubMed: 30583500
DOI: 10.3390/nu11010025 -
Nature Metabolism May 2021Non-alcoholic fatty liver disease (NAFLD), the most prevalent liver pathology worldwide, is intimately linked with obesity and type 2 diabetes. Liver inflammation is a... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD), the most prevalent liver pathology worldwide, 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 signalling 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 use of brown and beige adipocytes and UCP1 extends beyond thermogenesis and may be leveraged to antagonize NAFLD and SUCNR1-dependent liver inflammation.
Topics: Adipose Tissue, Beige; Adipose Tissue, White; Animals; Disease Susceptibility; Extracellular Space; Glucose; Glucose Intolerance; Hepatitis; Humans; Metabolic Networks and Pathways; Non-alcoholic Fatty Liver Disease; Receptors, G-Protein-Coupled; Succinic Acid; Uncoupling Protein 1
PubMed: 34002097
DOI: 10.1038/s42255-021-00389-5 -
Journal of Biomedical Science Nov 2022Succinate is a tricarboxylic acid (TCA) cycle intermediate normally confined to the mitochondrial matrix. It is a substrate of succinate dehydrogenase (SDH). Mutation of... (Review)
Review
Succinate is a tricarboxylic acid (TCA) cycle intermediate normally confined to the mitochondrial matrix. It is a substrate of succinate dehydrogenase (SDH). Mutation of SDH subunits (SDHD and SDHB) in hereditary tumors such as paraganglioma or reduction of SDHB expression in cancer results in matrix succinate accumulation which is transported to cytoplasma and secreted into the extracellular milieu. Excessive cytosolic succinate is known to stabilize hypoxia inducible factor-1α (HIF-1α) by inhibiting prolyl hydroxylase. Recent reports indicate that cancer-secreted succinate enhances cancer cell migration and promotes cancer metastasis by activating succinate receptor-1 (SUCNR-1)-mediated signaling and transcription pathways. Cancer-derived extracellular succinate enhances cancer cell and macrophage migration through SUCNR-1 → PI-3 K → HIF-1α pathway. Extracellular succinate induces tumor angiogenesis through SUCNR-1-mediated ERK1/2 and STAT3 activation resulting in upregulation of vascular endothelial growth factor (VEGF) expression. Succinate increases SUCNR-1 expression in cancer cells which is considered as a target for developing new anti-metastasis drugs. Furthermore, serum succinate which is elevated in cancer patients may be a theranostic biomarker for selecting patients for SUCNR-1 antagonist therapy.
Topics: Humans; Neovascularization, Pathologic; Paraganglioma; Succinates; Succinic Acid; Vascular Endothelial Growth Factor A; Neoplasms; Neoplasm Metastasis; Extracellular Space
PubMed: 36344992
DOI: 10.1186/s12929-022-00878-z -
Cell Reports Jan 2019We demonstrated the metabolic benefits of Parabacteroides distasonis (PD) on decreasing weight gain, hyperglycemia, and hepatic steatosis in ob/ob and high-fat diet...
We demonstrated the metabolic benefits of Parabacteroides distasonis (PD) on decreasing weight gain, hyperglycemia, and hepatic steatosis in ob/ob and high-fat diet (HFD)-fed mice. Treatment with live P. distasonis (LPD) dramatically altered the bile acid profile with elevated lithocholic acid (LCA) and ursodeoxycholic acid (UDCA) and increased the level of succinate in the gut. In vitro cultivation of PD demonstrated its capacity to transform bile acids and production of succinate. Succinate supplementation in the diet decreased hyperglycemia in ob/ob mice via the activation of intestinal gluconeogenesis (IGN). Gavage with a mixture of LCA and UDCA reduced hyperlipidemia by activating the FXR pathway and repairing gut barrier integrity. Co-treatment with succinate and LCA/UDCA mirrored the benefits of LPD. The binding target of succinate was identified as fructose-1,6-bisphosphatase, the rate-limiting enzyme in IGN. The succinate and secondary bile acids produced by P. distasonis played key roles in the modulation of host metabolism.
Topics: Animals; Bacterial Proteins; Bacteroidetes; Bile Acids and Salts; Gastrointestinal Microbiome; Humans; Mice; Obesity; Succinic Acid
PubMed: 30605678
DOI: 10.1016/j.celrep.2018.12.028 -
Mucosal Immunology Jan 2019Succinate, an intermediate of the tricarboxylic acid cycle, is accumulated in inflamed areas and its signaling through succinate receptor (SUCNR1) regulates immune...
Succinate, an intermediate of the tricarboxylic acid cycle, is accumulated in inflamed areas and its signaling through succinate receptor (SUCNR1) regulates immune function. We analyze SUCNR1 expression in the intestine of Crohn's disease patients and its role in murine intestinal inflammation and fibrosis. We show that both serum and intestinal succinate levels and SUCNR1 expression in intestinal surgical resections were higher in CD patients than in controls. SUCNR1 co-localized with CD86, CD206, and α-SMA+ cells in human intestine and we found a positive and significant correlation between SUCNR1 and α-SMA expression. In human isolated fibroblasts from CD patients SUCNR1 expression was higher than in those from controls and treatment with succinate increased SUCNR1 expression, fibrotic markers and inflammatory cytokines through SUCNR1. This receptor modulated the expression of pro-inflammatory cytokines in resting murine macrophages, macrophage polarization and fibroblast activation and Sucnr1 mice were protected against both acute TNBS-colitis and intestinal fibrosis induced by the heterotopic transplant of colonic tissue. We demonstrate increased succinate levels in serum and SUCNR1 expression in intestinal tissue of CD patients and show a role for SUCNR1 in murine intestinal inflammation and fibrosis.
Topics: Adolescent; Adult; Animals; Cells, Cultured; Colitis; Crohn Disease; Disease Models, Animal; Female; Fibrosis; Humans; Inflammation; Intestinal Mucosa; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, G-Protein-Coupled; Succinic Acid; Young Adult
PubMed: 30279517
DOI: 10.1038/s41385-018-0087-3