Neutrophils-derived itaconate facilitates viral infection via alkylating GDI2 II
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE249683 | GEO | 2024/06/01
REPOSITORIES: GEO
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Project description:To investigate the role of Irg1-itaconate or Hemin in macrophages, bone marrow-derived macrophages (BMDMs) from WT mice and Irg1 KO mice were extracted and cultured. After 7 days of cells culture, the BMDMs from WT mice were treated 120 μM 4-octyl itaconate (4-OI) for 15 h, 15 μM Hemin for 12 h, and the BMDMs from Irg1 KO mice and WT mice were treated Vehicle for 12 h. We then performed gene expression profiling analysis using data obtained from RNA-seq of 4-OI, Hemin or vehicle treated WT BMDMs and Irg1 KO BMDMs.
2024-06-28 | GSE221734 | GEO
Project description:Gene expression in LPS-stimulated, LPS-tolerized or non-tolerized WT and Irg1-deficient BMDMs
2021-04-20 | GSE164383 | GEO
Project description:Neutrophils-derived itaconate facilitates viral infection via alkylating GDI2 II
| PRJNA1050190 | ENA
Project description:Itaconate is a metabolite naturally produced in large amounts in macrophages after exposure to immune stimulation. Following the discovery of itaconate’s immunoregulatory properties, several ester derivatives of this dicarboxylic acid were designed to further examine its role. We evaluated the metabolic, electrophilic, and immunologic profiles of macrophages treated with unmodified itaconate and a panel of itaconate derivatives. We found that only unmodified itaconate strongly enhances LPS-induced IFNb secretion after 12h pre-treatment. Thus, we compared the transcriptional profile of wild type and Irg1-/- cells, which are unable to produce itaconate, after 24h LPS stimulation. We find that cells lacking itaconate have impaired downstream type I interferon signaling, and that addition of itaconate Irg1-/- BMDMs restores this signaling back to levels comparable to wild type. This data highlights the role of itaconate as an immunoregulatory metabolite, and highlights the importance of using unmodified itaconate or genetic knockout models in future mechanistic studies.
2020-05-15 | GSE145950 | GEO
Project description:Immune-response gene 1 (IRG1) transcription is rapidly induced by pathogen infections and inflammatory conditions primarily in cells of myeloid lineage. Deletion of Irg1 in mice causes severe defects in response to bacterial and viral infection and rapid death. IRG1 encodes a mitochondrial metabolic enzyme, aconitate decarboxylase 1 (ACOD1), that catalyzes the decarboxylation of cis-aconitate, a tricarboxylic acid cycle intermediate, to produce the anti-inflammatory metabolite itaconic acid (ITA). ITA can inhibit SDH5, resulting in elevated levels of succinate and metabolic reprogramming, or alkylate protein cysteine residues to induce electrophilic stress response mediated by NRF2 and IκBζ. Here we show that ITA is an antagonist of α-ketoglutarate (α-KG) and a potent inhibitor of α-KG/Fe2+-dependent TET family of DNA dioxygenases. In vitro, ITA binds to TET2 and inhibits the catalytic activity of TET2 and, reciprocally, α-KG blocks ITA binding to and inhibition of TET2. In vivo, lipopolysaccharides (LPS) treatment, which induces IRG1 expression and causes the intracellular accumulation of ITA, inhibits TET activity in Irg1-WT, but not Irg1-KO macrophages. Moreover, TET2 is a major target of ITA function in suppressing LPS-induced genes. LPS stimulates p65 NF-κB/RelA to bind with and recruit TET2 to hydroxymethylate and activate the Nfkbiz gene, which encodes IκBζ. Our results thus identify a physiological metabolite inhibitor of TET enzymes and reveal a novel mechanism for the anti-inflammatory function of ITA through dampening TET2-mediated NF-κB signaling.
2022-01-10 | GSE158580 | GEO
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:Immune-Responsive Gene 1 (Irg1) is a mitochondrial enzyme that produces itaconate under inflammatory conditions principally in cells of myeloid lineage. Cell culture studies suggest that itaconate regulates inflammation through inhibitory effects on cytokine and reactive oxygen species production. To evaluate the functions of Irg1 in vivo, we challenged wild-type (WT) and Irg1 KO mice with Mycobacterium tuberculosis (Mtb) and monitored disease progression. Irg1 KO but not WT mice succumbed rapidly to Mtb, and mortality was associated with increased infection, inflammation, and pathology. Infection of LysM-Cre Irg1 flox, MPR8-Cre Irg1 flox, and CD11c-Cre Irg1 flox conditional knockout mice along with neutrophil depletion experiments revealed a role for Irg1 in alveolar macrophages and LysM+ myeloid cells in preventing neutrophil-mediated immunopathology and disease. RNA-seq analyses suggest that Irg1 and its production of itaconate temper Mtb-induced inflammatory responses in myeloid cells at the transcriptional level. Thus, Irg1 modulates inflammation to curtail Mtb-induced lung disease.
2017-08-30 | GSE98456 | GEO
Project description:The tumor microenvironment possesses multiple overlapping mechanisms that suppress anti-tumor immunity. Itaconate is a metabolite produced from the Krebs cycle intermediate cis-aconitate by the activity of immune-responsive gene 1 (IRG1). While it is known to be immune modulatory, the role of itaconate in anti-tumor immunity is unclear. Here, we demonstrate that myeloid-derived suppressor cells (MDSCs) secreted itaconate that can be taken up by CD8+ T cells and suppress their proliferation, cytokine production, and cytolytic activity. Metabolite profiling, stable-isotope tracing and metabolite supplementation studies indicated that itaconate suppressed biosynthesis of aspartate and serine/glycine in CD8+ T cells to attenuate their proliferation. Moreover, stromal deletion of IRG1 in mice bearing allografted tumors resulted in decreased tumor growth, inhibited the immune suppressive activities of MDSCs, reduced levels of itaconate in tumors, promoted anti-tumor immunity of CD8+ T cells, and enhanced the anti-tumor activity of anti-PD-1 antibody treatment. Importantly, we found a significant negative correlation between IRG1 expression and response to PD-1 immune checkpoint blockade in melanoma patients. Our findings not only reveal a previously unknown role of itaconate as an immune checkpoint metabolite secreted from MDSCs to suppress CD8+ T cells, but also establish IRG1 as a novel myeloid-selective target in immunometabolism to promote anti-tumor immunity and enhance the efficacy of immune checkpoint protein blockade.
2022-11-15 | GSE190028 | GEO
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