Similar Datasets
Project description:Itaconate-producing neutrophils regulate local and systemic inflammation following trauma
| PRJNA913089 | ENA
Project description:Neutrophils-derived itaconate facilitates viral infection via alkylating GDI2 II
| PRJNA1050190 | ENA
Project description:Neutrophils are critical in the host defense against Staphylococcus aureus, a major human pathogen. However, even in the setting of a robust neutrophil response, S. aureus can cause persistent infection. Here we demonstrate that S. aureus impairs neutrophil function by triggering the production of the anti-inflammatory metabolite, itaconate. The enzyme that synthesizes itaconate, Irg1, is selectively expressed in neutrophils during S. aureus pneumonia. Itaconate inhibits neutrophil glycolysis and oxidative burst, which impairs survival and bacterial killing. In a murine pneumonia model, neutrophil Irg1 expression protects critical lung cell populations from oxidative stress but compromises bacterial clearance. S. aureus is thus able to evade innate immune clearance by targeting neutrophil metabolism and inducing the production of the antiinflammatory metabolite itaconate.
2023-01-01 | GSE215195 | GEO
Project description:Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation mechanism 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 downstream pro-inflammatory IL-1β-HIF1a 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 via its effect on succinate dehydrogenase, by inhibiting conversion of succinate to fumarate. 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, changes in 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. Experiment 1: mature WT BMDM were treated for 12h with 0.25 mM dimethyl itaconate (DI) or vehicle (Unst) and then stimulated with LPS (E. coli 0111:B4; 100 ng/ml, 4h) (DI+LPS; LPS); Experiment 2: mature Irg1-/- BMDM were stimulated with LPS (E. coli 0111:B4; 100 ng/ml) and murine recombinant IFNg (50 ng/ml) for 24h.
2016-07-01 | E-GEOD-82043 | biostudies-arrayexpress
Project description:One primary metabolic manifestation of inflammation is the diversion of cis-aconitate within the tricarboxylic acid (TCA) cycle to synthesize the immunometabolite itaconate. Itaconate is well established to possess immunomodulatory and metabolic effects within myeloid cells and lymphocytes, however, its effects in other organ systems during sepsis remain less clear. Utilizing Irg1 knockout mice that are deficient in synthesizing itaconate, we aimed at understanding the metabolic role of itaconate in the liver and systemically during sepsis. We find itaconate aids in lipid metabolism during sepsis. Specifically, Irg1 KO mice develop a heightened level of hepatic steatosis when induced with polymicrobial sepsis. Proteomics analysis reveal enhanced expression of enzymes involved in fatty acid oxidation in following 4-ocytl itaconate (4-OI) treatment in vitro. Downstream analysis reveals itaconate stabilizes the expression of the mitochondrial fatty acid uptake enzyme CPT1a, mediated by its hypoubiquitination. Chemoproteomic analysis revealed itaconate interacts with proteins involved in protein ubiquitination as a potential mechanism underlying its stabilizing effect on CPT1a. From a systemic perspective, we find itaconate deficiency triggers a hypothermic response following endotoxin stimulation, potentially mediated by brown adipose tissue (BAT) dysfunction. Finally, by use of metabolic cage studies, we demonstrate Irg1 KO mice rely more heavily on carbohydrates versus fatty acid sources for systemic fuel utilization in response to endotoxin treatment. Our data reveal a novel metabolic role of itaconate in modulating fatty acid oxidation during polymicrobial sepsis.
2024-01-29 | PXD047706 | Pride
Project description:This dataset was generated to confirm that +130 and +146 Da adducts observed in LPS-stimulated macrophages were produced by the itaconate metabolite. To this end, model proteins (bovine serum albumin and human KEAP1) were reacted in vitro with itaconate, and the correspondent adducts were analyzed by LC-MSMS
2021-07-22 | PXD019858 | Pride
Project description:Itaconate is an immunoregulatory metabolite produced by the mitochondrial enzyme immune-responsive gene 1 (IRG1) in inflammatory macrophages. We recently identified an important mechanism by which itaconate is released from inflammatory macrophages. However, it remains unknown whether extracellular itaconate is taken up by non-myeloid cells to exert immunoregulatory functions. Here, we used a custom-designed CRISPR screen to identify the dicarboxylate transporter solute carrier family 13 member 3 (SLC13A3) as an itaconate importer and to characterize the role of SLC13A3 in itaconate-improved hepatic antibacterial innate immunity. Functionally, liver-specific deletion of Slc13a3 impairs hepatic antibacterial innate immunity in vivo and in vitro. Mechanistically, itaconate uptake via SLC13A3 induces transcription factor EB (TFEB)-dependent lysosomal biogenesis and subsequently improves antibacterial innate immunity in murine hepatocytes. These findings identify SLC13A3 as a key itaconate importer in murine hepatocytes and will aid in the development of potent itaconate-based antibacterial therapeutics.
2024-07-08 | GSE230735 | GEO
Project description:This study used proteomic, biomechanical, and functional analyses to further define neutrophil heterogeneity in the context of SLE. Mass spectrometry proteomic and phosphoproteomic analyses were performed in healthy control normal density neutrophils (NDNs), SLE NDNs and in autologous SLE LDGs. Proteomic and phosphoproteomic differences were detected when comparing control to SLE neutrophils and when comparing SLE NDNs to SLE LDGs.
2021-11-04 | PXD021096 | Pride
Project description:#G017 Burn/Trauma Study. This is a Glue Grant Study comparison between gene expression analyses performed in eight trauma/burn subjects using either a buffy coat isolation of whole blood or using the PAXgene system Keywords: other
2004-04-24 | GSE1343 | GEO
Project description:Itaconate has emerged as a critical immunoregulatory metabolite. Here, we examined the therapeutic potential of itaconate in atherosclerosis. We found that both itaconate and the enzyme that synthesizes it, aconitate decarboxylase 1 (Acod1, also known as “immune-responsive gene 1”/IRG1) are upregulated during atherogenesis in mice. Here we analzyed the anatomy of atherosclerotic plaques from wildtype and Acod1-/- mice through single cell RNA-seq.
2024-02-14 | GSE235749 | GEO