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Succinate based polymers drive immunometabolism in dendritic cells to generate cancer immunotherapy.Journal of Controlled Release :... Jun 2023Boosting the metabolism of immune cells while restricting cancer cell metabolism is challenging. Herein, we report that using biomaterials for the controlled delivery of...
Boosting the metabolism of immune cells while restricting cancer cell metabolism is challenging. Herein, we report that using biomaterials for the controlled delivery of succinate metabolite to phagocytic immune cells activates them and modulates their metabolism in the presence of metabolic inhibitors. In young immunocompetent mice, polymeric microparticles, with succinate incorporated in the backbone, induced strong pro-inflammatory anti-melanoma responses. Administration of poly(ethylene succinate) (PES MP)-based vaccines and glutaminase inhibitor to young immunocompetent mice with aggressive and large, established B16F10 melanoma tumors increased their survival three-fold, a result of increased cytotoxic T cells expressing RORγT (Tc17). Mechanistically, PES MPs directly modulate glutamine and glutamate metabolism, upregulate succinate receptor SUCNR1, activate antigen presenting cells through and HIF-1alpha, TNFa and TSLP-signaling pathways, and are dependent on alpha-ketoglutarate dehydrogenase for their activity, which demonstrates correlation of succinate delivery and these pathways. Overall, our findings suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies.
Topics: Animals; Mice; Polymers; Succinic Acid; Immunotherapy; Signal Transduction; Melanoma; Dendritic Cells; Cancer Vaccines
PubMed: 37182805
DOI: 10.1016/j.jconrel.2023.05.014 -
The EMBO Journal Jun 2022Influenza virus infection causes considerable morbidity and mortality, but current therapies have limited efficacy. We hypothesized that investigating the metabolic...
Influenza virus infection causes considerable morbidity and mortality, but current therapies have limited efficacy. We hypothesized that investigating the metabolic signaling during infection may help to design innovative antiviral approaches. Using bronchoalveolar lavages of infected mice, we here demonstrate that influenza virus induces a major reprogramming of lung metabolism. We focused on mitochondria-derived succinate that accumulated both in the respiratory fluids of virus-challenged mice and of patients with influenza pneumonia. Notably, succinate displays a potent antiviral activity in vitro as it inhibits the multiplication of influenza A/H1N1 and A/H3N2 strains and strongly decreases virus-triggered metabolic perturbations and inflammatory responses. Moreover, mice receiving succinate intranasally showed reduced viral loads in lungs and increased survival compared to control animals. The antiviral mechanism involves a succinate-dependent posttranslational modification, that is, succinylation, of the viral nucleoprotein at the highly conserved K87 residue. Succinylation of viral nucleoprotein altered its electrostatic interactions with viral RNA and further impaired the trafficking of viral ribonucleoprotein complexes. The finding that succinate efficiently disrupts the influenza replication cycle opens up new avenues for improved treatment of influenza pneumonia.
Topics: Animals; Antiviral Agents; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza, Human; Mice; Nucleocapsid Proteins; Nucleoproteins; Orthomyxoviridae Infections; Pneumonia; Succinic Acid; Virus Replication
PubMed: 35506364
DOI: 10.15252/embj.2021108306 -
Endocrinology and Metabolism (Seoul,... Aug 2023Hepatic stellate cells (HSCs) are the major cells which play a pivotal role in liver fibrosis. During injury, extracellular stimulators can induce HSCs...
BACKGRUOUND
Hepatic stellate cells (HSCs) are the major cells which play a pivotal role in liver fibrosis. During injury, extracellular stimulators can induce HSCs transdifferentiated into active form. Phloretin showed its ability to protect the liver from injury, so in this research we would like to investigate the effect of phloretin on succinate-induced HSCs activation in vitro and liver fibrosis in vivo study.
METHODS
In in vitro, succinate was used to induce HSCs activation, and then the effect of phloretin on activated HSCs was examined. In in vivo, succinate was used to generated liver fibrosis in mouse and phloretin co-treated to check its protection on the liver.
RESULTS
Phloretin can reduce the increase of fibrogenic markers and inhibits the proliferation, migration, and contraction caused by succinate in in vitro experiments. Moreover, an upregulation of proteins associated with aerobic glycolysis occurred during the activation of HSCs, which was attenuated by phloretin treatment. In in vivo experiments, intraperitoneal injection of phloretin decreased expression of fibrotic and glycolytic markers in the livers of mice with sodium succinate diet-induced liver fibrosis. These results suggest that aerobic glycolysis plays critical role in activation of HSCs and succinate can induce liver fibrosis in mice, whereas phloretin has therapeutic potential for treating hepatic fibrosis.
CONCLUSION
Intraperitoneal injection of phloretin attenuated succinate-induced hepatic fibrosis and alleviates the succinate-induced HSCs activation.
Topics: Mice; Animals; Succinic Acid; Phloretin; Hepatic Stellate Cells; Liver Cirrhosis
PubMed: 37533177
DOI: 10.3803/EnM.2023.1661 -
Cell Reports Sep 2022Periodontal disease (PD) is one of the most common inflammatory diseases in humans and is initiated by an oral microbial dysbiosis that stimulates inflammation and bone...
Periodontal disease (PD) is one of the most common inflammatory diseases in humans and is initiated by an oral microbial dysbiosis that stimulates inflammation and bone loss. Here, we report an abnormal elevation of succinate in the subgingival plaque of subjects with severe PD. Succinate activates succinate receptor-1 (SUCNR1) and stimulates inflammation. We detected SUCNR1 expression in the human and mouse periodontium and hypothesize that succinate activates SUCNR1 to accelerate periodontitis through the inflammatory response. Administration of exogenous succinate enhanced periodontal disease, whereas SUCNR1 knockout mice were protected from inflammation, oral dysbiosis, and subsequent periodontal bone loss in two different models of periodontitis. Therapeutic studies demonstrated that a SUCNR1 antagonist inhibited inflammatory events and osteoclastogenesis in vitro and reduced periodontal bone loss in vivo. Our study reveals succinate's effect on periodontitis pathogenesis and provides a topical treatment for this disease.
Topics: Alveolar Bone Loss; Animals; Dysbiosis; Humans; Inflammation; Mice; Mice, Knockout; Periodontal Diseases; Periodontitis; Succinic Acid
PubMed: 36130514
DOI: 10.1016/j.celrep.2022.111389 -
Cellular and Molecular Life Sciences :... Jun 2018In the last decade, metabolism has been recognized as a major determinant of immunological processes. During an inflammatory response, macrophages undergo striking... (Review)
Review
In the last decade, metabolism has been recognized as a major determinant of immunological processes. During an inflammatory response, macrophages undergo striking changes in their metabolism. This metabolic reprogramming is governed by a complex interplay between metabolic enzymes and metabolites of different pathways and represents the basis for proper macrophage function. It is now evident that these changes go far beyond the well-known Warburg effect and the perturbation of metabolic targets is being investigated as a means to treat infections and auto-immune diseases. In the present review, we will aim to provide an overview of the metabolic responses during proinflammatory macrophage activation and show how these changes modulate the immune response.
Topics: Animals; Communicable Diseases; Energy Metabolism; Glycolysis; Humans; Inflammation; Macrophage Activation; Macrophages; Metabolic Networks and Pathways; Reactive Oxygen Species; Succinates; Succinic Acid
PubMed: 29502308
DOI: 10.1007/s00018-018-2784-1 -
American Journal of Physiology. Cell... Feb 2023Succinate has long been known to be only an intermediate product of the tricarboxylic acid cycle until identified as a natural ligand for SUCNR1 in 2004. SUCNR1 is...
Succinate has long been known to be only an intermediate product of the tricarboxylic acid cycle until identified as a natural ligand for SUCNR1 in 2004. SUCNR1 is widely expressed throughout the body, especially in the kidney. Abnormally elevated succinate is associated with many diseases, including obesity, type 2 diabetes, nonalcoholic fatty liver disease, and ischemia injury, but it is not known whether succinate can cause kidney damage. This study showed that succinate induced apparent renal injury after treatment for 12 wk, characterized by a reduction in 24 h urine and the significant detachment of the brush border of proximal tubular epithelial cells, tubular dilation, cast formation, and vacuolar degeneration of tubular cells in succinate-treated mice. Besides, succinate caused tubular epithelial cell apoptosis in kidneys and HK-2 cells. Mechanistically, succinate triggered cell apoptosis via SUCNR1 activation. In addition, succinate upregulated ERK by binding to SUCNR1, and inhibition of ERK using PD98059 abolished the proapoptotic effects of succinate in HK-2 cells. In summary, our study provides the first evidence that succinate acts as a risk factor and contributes to renal injury, and further research is required to discern the pathological effects of succinate on renal functions.
Topics: Animals; Mice; Apoptosis; Diabetes Mellitus, Type 2; Epithelial Cells; Kidney; Receptors, G-Protein-Coupled; Succinates; Succinic Acid
PubMed: 36622070
DOI: 10.1152/ajpcell.00327.2022 -
American Journal of Physiology.... Apr 2023Succinate is released by skeletal muscle during exercise and activates /GPR91. Signaling of SUCNR1 is involved in metabolite-sensing paracrine communication in skeletal...
Succinate is released by skeletal muscle during exercise and activates /GPR91. Signaling of SUCNR1 is involved in metabolite-sensing paracrine communication in skeletal muscle during exercise. However, the specific cell types responding to succinate and the directionality of communication are unclear. We aim to characterize the expression of SUCNR1 in human skeletal muscle. De novo analysis of transcriptomic datasets demonstrated that mRNA is expressed in immune, adipose, and liver tissues, but scarce in skeletal muscle. In human tissues, mRNA was associated with macrophage markers. Single-cell RNA sequencing and fluorescent RNAscope demonstrated that in human skeletal muscle, mRNA is not expressed in muscle fibers but coincided with macrophage populations. Human M2-polarized macrophages exhibit high levels of mRNA and stimulation with selective agonists of SUCNR1 triggered Gq- and Gi-coupled signaling. Primary human skeletal muscle cells were unresponsive to SUCNR1 agonists. In conclusion, SUCNR1 is not expressed in muscle cells and its role in the adaptive response of skeletal muscle to exercise is most likely mediated via paracrine mechanisms involving M2-like macrophages within the muscle. Macrophages but not skeletal muscle cells respond to extracellular succinate via SUCNR1/GPR91.
Topics: Humans; Muscles; Obesity; Receptors, G-Protein-Coupled; Signal Transduction; Succinic Acid
PubMed: 36812387
DOI: 10.1152/ajpendo.00009.2023 -
PLoS Pathogens Aug 2022Macrophages restrict bacterial infection partly by stimulating phagocytosis and partly by stimulating release of cytokines and complement components. Here, we treat...
Macrophages restrict bacterial infection partly by stimulating phagocytosis and partly by stimulating release of cytokines and complement components. Here, we treat macrophages with LPS and a bacterial pathogen, and demonstrate that expression of cytokine IL-1β and bacterial phagocytosis increase to a transient peak 8 to 12 h post-treatment, while expression of complement component 3 (C3) continues to rise for 24 h post-treatment. Metabolomic analysis suggests a correlation between the cellular concentrations of succinate and IL-1β and of inosine and C3. This may involve a regulatory feedback mechanism, whereby succinate stimulates and inosine inhibits HIF-1α through their competitive interactions with prolyl hydroxylase. Furthermore, increased level of inosine in LPS-stimulated macrophages is linked to accumulation of adenosine monophosphate and that exogenous inosine improves the survival of bacterial pathogen-infected mice and tilapia. The implications of these data suggests potential therapeutic tools to prevent, manage or treat bacterial infections.
Topics: Animals; Bacterial Infections; Cytokines; Inosine; Lipopolysaccharides; Mice; Phagocytosis; Succinic Acid
PubMed: 36026499
DOI: 10.1371/journal.ppat.1010796 -
BioMed Research International 2013Succinate is a promising chemical which has wide applications and can be produced by biological route. The history of the biosuccinate production shows that the joint... (Review)
Review
Succinate is a promising chemical which has wide applications and can be produced by biological route. The history of the biosuccinate production shows that the joint effort of different metabolic engineering approaches brings successful results. In order to enhance the succinate production, multiple metabolical strategies have been sought. In this review, different overproducers for succinate production, including natural succinate overproducers and metabolic engineered overproducers, are examined and the metabolic engineering strategies and performances are discussed. Modification of the mechanism of substrate transportation, knocking-out genes responsible for by-products accumulation, overexpression of the genes directly involved in the pathway, and improvement of internal NADH and ATP formation are some of the strategies applied. Combination of the appropriate genes from homologous and heterologous hosts, extension of substrate, integrated production of succinate, and other high-value-added products are expected to bring a desired objective of producing succinate from renewable resources economically and efficiently.
Topics: Biological Transport; Genetic Engineering; Metabolic Engineering; Metabolic Networks and Pathways; Succinic Acid
PubMed: 23691505
DOI: 10.1155/2013/538790 -
Haematologica Oct 2018Succinate is an essential intermediate of the tricarboxylic acid cycle that exerts pleiotropic roles beyond metabolism in both physiological and pathological conditions.... (Review)
Review
Succinate is an essential intermediate of the tricarboxylic acid cycle that exerts pleiotropic roles beyond metabolism in both physiological and pathological conditions. Recent evidence obtained in mouse models shows its essential role regulating blood cell function through various mechanisms that include pseudohypoxia responses by hypoxia-inducible factor-1α activation, post-translational modifications like succinylation, and communication mediated by succinate receptor 1. Hence, succinate links metabolism to processes like gene expression and intercellular communication. Interestingly, succinate plays key dual roles during inflammatory responses, leading to net inflammation or anti-inflammation depending on factors like the cellular context. Here, we further discuss current suggestions of the possible contribution of succinate to blood stem cell function and blood formation. Further study will be required in the future to better understand succinate biology in blood cells. This promising field may open new avenues to modulate inflammatory responses and to preserve blood cell homeostasis in the clinical setting.
Topics: Animals; Gene Expression Regulation; Hematopoietic Stem Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Protein Processing, Post-Translational; Receptors, G-Protein-Coupled; Succinic Acid
PubMed: 29954939
DOI: 10.3324/haematol.2018.196097