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Cell Death and Differentiation Feb 2024Efferocytosis and metabolic reprogramming of macrophages play crucial roles in myocardial infarction (MI) repair. TREM2 has been proven to participate in phagocytosis...
Efferocytosis and metabolic reprogramming of macrophages play crucial roles in myocardial infarction (MI) repair. TREM2 has been proven to participate in phagocytosis and metabolism, but how it modulates myocardial infarction remains unclear. In this study, we showed that macrophage-specific TREM2 deficiency worsened cardiac function and impaired post-MI repair. Using RNA-seq, protein and molecular docking, and Targeted Metabolomics (LC-MS), our data demonstrated that macrophages expressing TREM2 exhibited decreased SLC25A53 transcription through the SYK-SMAD4 signaling pathway after efferocytosis, which impaired NAD transport into mitochondria, downregulated SLC25A53 thereby causing the breakpoint in the TCA cycle and subsequently increased itaconate production. In vitro experiments confirmed that itaconate secreted by TREM2 macrophages inhibited cardiomyocyte apoptosis and promoted fibroblast proliferation. Conversely, overexpression of TREM2 in macrophages could improve cardiac function. In summary, our study reveals a novel role for macrophage-specific TREM2 in MI, connecting efferocytosis to immune metabolism during cardiac repair.
Topics: Animals; Mice; Macrophages; Mice, Inbred C57BL; Molecular Docking Simulation; Myocardial Infarction; Succinates; Humans
PubMed: 38182899
DOI: 10.1038/s41418-023-01252-8 -
Metabolism: Clinical and Experimental Aug 2023Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond...
OBJECTIVE
Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond the activation of hepatic stellate cells remains unexplored. We investigated the succinate/SUCNR1 axis in the context of NAFLD specifically in hepatocytes.
METHODS
We studied the phenotype of wild-type and Sucnr1 mice fed a choline-deficient high-fat diet to induce non-alcoholic steatohepatitis (NASH), and explored the function of SUCNR1 in murine primary hepatocytes and human HepG2 cells treated with palmitic acid. Lastly, plasma succinate and hepatic SUCNR1 expression were analyzed in four independent cohorts of patients in different NAFLD stages.
RESULTS
Sucnr1 was upregulated in murine liver and primary hepatocytes in response to diet-induced NASH. Sucnr1 deficiency provoked both beneficial (reduced fibrosis and endoplasmic reticulum stress) and detrimental (exacerbated steatosis and inflammation and reduced glycogen content) effects in the liver, and disrupted glucose homeostasis. Studies in vitro revealed that hepatocyte injury increased Sucnr1 expression, which when activated improved lipid and glycogen homeostasis in damaged hepatocytes. In humans, SUCNR1 expression was a good determinant of NAFLD progression to advanced stages. In a population at risk of NAFLD, circulating succinate was elevated in patients with a fatty liver index (FLI) ≥60. Indeed, succinate had good predictive value for steatosis diagnosed by FLI, and improved the prediction of moderate/severe steatosis through biopsy when added to an FLI algorithm.
CONCLUSIONS
We identify hepatocytes as target cells of extracellular succinate during NAFLD progression and uncover a hitherto unknown function for SUCNR1 as a regulator of hepatocyte glucose and lipid metabolism. Our clinical data highlight the potential of succinate and hepatic SUCNR1 expression as markers to diagnose fatty liver and NASH, respectively.
Topics: Animals; Humans; Mice; Disease Models, Animal; Fibrosis; Glucose; Glycogen; Hepatocytes; Liver; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Succinates
PubMed: 37315889
DOI: 10.1016/j.metabol.2023.155630 -
Advanced Science (Weinheim,... Oct 2023Mitochondria are the pivot organelles to control metabolism and energy homeostasis. The capacity of mitochondrial metabolic adaptions to cold stress is essential for...
Mitochondria are the pivot organelles to control metabolism and energy homeostasis. The capacity of mitochondrial metabolic adaptions to cold stress is essential for adipocyte thermogenesis. How brown adipocytes keep mitochondrial fitness upon a challenge of cold-induced oxidative stress has not been well characterized. This manuscript shows that IFI27 plays an important role in cristae morphogenesis, keeping intact succinate dehydrogenase (SDH) function and active fatty acid oxidation to sustain thermogenesis in brown adipocytes. IFI27 protein interaction map identifies SDHB and HADHA as its binding partners. IFI27 physically links SDHB to chaperone TNF receptor associated protein 1 (TRAP1), which shields SDHB from oxidative damage-triggered degradation. Moreover, IFI27 increases hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) catalytic activity in β-oxidation pathway. The reduced SDH level and fatty acid oxidation in Ifi27-knockout brown fat results in impaired oxygen consumption and defective thermogenesis. Thus, IFI27 is a novel regulator of mitochondrial metabolism and thermogenesis.
Topics: Succinic Acid; Adipocytes, Brown; Adipose Tissue, Brown; Fatty Acids; Thermogenesis
PubMed: 37544897
DOI: 10.1002/advs.202301855 -
Circulation Research Dec 2023
Topics: Succinic Acid; Succinates; Heart
PubMed: 38112098
DOI: 10.1161/CIRCRESAHA.123.323651 -
ELife Jul 2023The hypothalamus-pituitary-adrenal (HPA) axis is activated in response to inflammation leading to increased production of anti-inflammatory glucocorticoids by the...
The hypothalamus-pituitary-adrenal (HPA) axis is activated in response to inflammation leading to increased production of anti-inflammatory glucocorticoids by the adrenal cortex, thereby representing an endogenous feedback loop. However, severe inflammation reduces the responsiveness of the adrenal gland to adrenocorticotropic hormone (ACTH), although the underlying mechanisms are poorly understood. Here, we show by transcriptomic, proteomic, and metabolomic analyses that LPS-induced systemic inflammation triggers profound metabolic changes in steroidogenic adrenocortical cells, including downregulation of the TCA cycle and oxidative phosphorylation, in mice. Inflammation disrupts the TCA cycle at the level of succinate dehydrogenase (SDH), leading to succinate accumulation and disturbed steroidogenesis. Mechanistically, IL-1β reduces SDHB expression through upregulation of DNA methyltransferase 1 (DNMT1) and methylation of the promoter. Consequently, increased succinate levels impair oxidative phosphorylation and ATP synthesis and enhance ROS production, leading to reduced steroidogenesis. Together, we demonstrate that the IL-1β-DNMT1-SDHB-succinate axis disrupts steroidogenesis. Our findings not only provide a mechanistic explanation for adrenal dysfunction in severe inflammation, but also offer a potential target for therapeutic intervention.
Topics: Mice; Animals; Succinic Acid; Proteomics; Glucocorticoids; Adrenocorticotropic Hormone; Inflammation
PubMed: 37449973
DOI: 10.7554/eLife.83064 -
Cell Reports Sep 2023The cyclic guanosine monophosphate adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) axis plays a vital role in defending foreign pathogens...
The cyclic guanosine monophosphate adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) axis plays a vital role in defending foreign pathogens and maintaining immune homeostasis. While substantial advances have been made in understanding the metabolic changes that occur during macrophage activation, little is known about how these metabolic changes affect the cGAS-STING axis. In this study, we identify that 4-octyl itaconate (4-OI), a derivative of itaconate, inhibits the activation of cGAS-STING. Furthermore, we show that 4-OI inhibits cGAS-STING-related antiviral immune responses and autoimmune inflammation. However, we find that endogenous itaconate does not affect cGAS-STING activation, indicating that 4-OI and itaconate function differently. Mechanistically, we find that 4-OI directly alkylates STING at Cys91, blocking STING palmitoylation and oligomerization. The alkylation of STING by 4-OI represents another type of post-translational modifications (PTMs) of STING. Our findings reveal a mechanism by which cGAS-STING function is regulated through 4-OI alkylation and provide insights into the crosstalk between different kinds of PTMs.
Topics: Lipoylation; Nucleotidyltransferases; Succinates
PubMed: 37624697
DOI: 10.1016/j.celrep.2023.113040 -
Inflammation Aug 2023With advances in immunometabolic studies, more and more evidence has shown that metabolic changes profoundly affect the immune function of macrophages. The tricarboxylic... (Review)
Review
With advances in immunometabolic studies, more and more evidence has shown that metabolic changes profoundly affect the immune function of macrophages. The tricarboxylic acid cycle is a central metabolic pathway of cells. Itaconate, a byproduct of the tricarboxylic acid cycle, is an emerging metabolic small molecule that regulates macrophage inflammation and has received much attention for its potent anti-inflammatory effects in recent years. Itaconate regulates macrophage function through multiple mechanisms and has demonstrated promising therapeutic potential in a variety of immune and inflammatory diseases. New progress in the mechanism of itaconate continues to be made, but it also implies complexity in its action and a need for a more comprehensive understanding of its role in macrophages. In this article, we review the primary mechanisms and current research progress of itaconate in regulating macrophage immune metabolism, hoping to provide new insights and directions for future research and disease treatment.
Topics: Succinates; Macrophages; Adjuvants, Immunologic; Immunologic Factors
PubMed: 37142886
DOI: 10.1007/s10753-023-01819-0 -
Nature Communications Dec 2023Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived...
Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8 T-cell exhaustion. Our results show that the knockout of immune-responsive gene 1 (IRG1), responsible for itaconate production, suppresses HCC progression. Irg1 knockout leads to a decreased proportion of PD-1 and TIM-3 CD8 T cells. Deletion or adoptive transfer of CD8 T cells shows that IRG1-promoted tumorigenesis depends on CD8 T-cell exhaustion. Mechanistically, itaconate upregulates PD-1 and TIM-3 expression levels by promoting succinate-dependent H3K4me3 of the Eomes promoter. Finally, ibuprofen is found to inhibit HCC progression by targeting IRG1/itaconate-dependent tumor immunoevasion, and high IRG1 expression in macrophages predicts poor prognosis in HCC patients. Taken together, our results uncover an epigenetic link between itaconate and HCC and suggest that targeting IRG1 or itaconate might be a promising strategy for HCC treatment.
Topics: Humans; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; Liver Neoplasms; Hepatitis A Virus Cellular Receptor 2; Programmed Cell Death 1 Receptor; T-Cell Exhaustion; Succinates; Epigenesis, Genetic
PubMed: 38071226
DOI: 10.1038/s41467-023-43988-4 -
Redox Biology Jun 2024Redox signaling, a mode of signal transduction that involves the transfer of electrons from a nucleophilic to electrophilic molecule, has emerged as an essential... (Review)
Review
Redox signaling, a mode of signal transduction that involves the transfer of electrons from a nucleophilic to electrophilic molecule, has emerged as an essential regulator of inflammatory macrophages. Redox reactions are driven by reactive oxygen/nitrogen species (ROS and RNS) and redox-sensitive metabolites such as fumarate and itaconate, which can post-translationally modify specific cysteine residues in target proteins. In the past decade our understanding of how ROS, RNS, and redox-sensitive metabolites control macrophage function has expanded dramatically. In this review, we discuss the latest evidence of how ROS, RNS, and metabolites regulate macrophage function and how this is dysregulated with disease. We highlight the key tools to assess redox signaling and important questions that remain.
Topics: Oxidation-Reduction; Macrophages; Humans; Reactive Nitrogen Species; Reactive Oxygen Species; Animals; Signal Transduction; Succinates
PubMed: 38615489
DOI: 10.1016/j.redox.2024.103123