MRNAseq of primary hepatocytes treated in vitro with Itaconate, Lipid, or Itaconate + Lipid
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE227900 | GEO | 2023/03/28
REPOSITORIES: GEO
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Project description:mRNAseq of primary hepatocytes treated in vitro with Itaconate, Lipid, or Itaconate + Lipid
| PRJNA947249 | ENA
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: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: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: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
Project description:Analysis of gene expression in human PBMCs infected with influenza A virus or Mock and treated with Itaconic acid, Dimethyl itaconate or 4-Octyl itaconate to investigate the effects itaconate have on transcriptional response in human PBMCs. We particularly looked at anti-inflammatory effects of itaconate in inflammation followed by Influenza A virus infection.
2021-10-31 | GSE162210 | GEO
Project description:Here, we report that macrophage-derived itaconate exerts a significant suppressive effect on dendritic cell (DC) function. To delve deeper into the impact of itaconate on DCs, we treated bone marrow-derived dendritic cells with 4-OI, a derivative of itaconate, and conducted RNA-seq analysis. Gene-set enrichment analysis (GSEA) of 4-OI-treated DCs showed a general downregulation of innate immunity and immune-response pathways.
2024-06-30 | GSE268402 | GEO
Project description:Bone remodeling is a highly dynamic process dependent on the precise coordination of osteoblasts and hematopoietic-cell derived osteoclasts. Emerging evidence indicates that cellular differentiation is associated with a metabolic rewiring in conjunction with the acquisition of specific effector functions. Changes in core metabolic pathways during osteoclastogenesis, however, are largely unexplored and it is unknown whether and how these processes are involved in bone homeostasis. We show that during differentiation preosteoclasts rearrange their tricarboxylic acid (TCA) cycle, a process crucially depending on both glucose and glutamine. This rearrangement is characterized by induction of immunoresponsive gene 1 (Irg1) and production of itaconate, which accumulates intra- and extracellularly. While the IRG1-itaconate axis is dispensable for osteoclast generationin vitroandin vivo, we demonstrate that itaconate stimulates osteoblasts by accelerating osteogenic differentiation, reducing proliferation and shifting ATP production from mitochondrial respiration to glycolysis. Additionally, supplementation of itaconate increases bone formation by boosting osteoblast activity in mice. Conversely,Irg1deficient mice exhibit decreased bone mass and have reduced osteoproliferative lesions in experimental arthritis. In summary, we identify itaconate, generated as a result of the metabolic rewiring during osteoclast differentiation, as a previously unrecognized regulator of the crosstalk between osteoclasts and osteoblasts
2024-07-24 | GSE236452 | GEO
Project description:A wide variety of electrophilic derivatives of the Kreb’s cycle-derived metabolite, itaconate, are immunomodulatory, yet these derivatives have overlapping and sometimes contradictory activities. Therefore, we generated a genetic system to interrogate the immunomodulatory functions of endogenously produced itaconate in human macrophages. Endogenous itaconate is driven by multiple innate signals restraining inflammatory cytokine production. Endogenous itaconate directly targets cysteine 13 in IRAK4 disrupting IRAK4 autophosphorylation and activation, drives the degradation of NFκB, and modulates global ubiquitination patterns. As a result, cells unable to make itaconate overproduce inflammatory cytokines such as TNFα, IL6, and IL-1β in response to these innate activators. In contrast, the production of IFNβ, downstream of LPS, requires the production of itaconate. These data demonstrate that itaconate is a critical arbiter of inflammatory cytokine production downstream of multiple innate signaling pathways laying the groundwork for the development of itaconate mimetics for the treatment of autoimmunity.
2024-07-17 | GSE272396 | GEO