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Itaconate modulates immune responses via inhibition of peroxiredoxin 5

ABSTRACT: Itaconate modulates immune responses via inhibition of peroxiredoxin 5

PROVIDER: PRJNA1163360 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30749839_1.fastq.gz	Fastqsanger.gz
	SRR30749839_2.fastq.gz	Fastqsanger.gz
	SRR30749840_1.fastq.gz	Fastqsanger.gz
	SRR30749840_2.fastq.gz	Fastqsanger.gz
	SRR30749841_1.fastq.gz	Fastqsanger.gz

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Itaconate modulates immune responses via inhibition of peroxiredoxins

Project description:Itaconate is a natural mild electrophile, able to modify free thiols in proteins upon activation. We submit two datasets investigating peptides modified by itaconate. Experiment001 contains data obtained from endogenous itaconate producing WT or itaconate incompetent Irg1-/- Bone marrow-derived macrophages stimulated with LPS for 24h. The second dataset from Experiment002 contains data obtained from WT Bone marrow-derived macrophages treated with media or 5 mM itaconic acid for 16h.

2023-11-28 | MSV000093522 | MassIVE

Itaconate modulates immune responses via inhibition of peroxiredoxin 5

Project description:Gene expression in WT BMDMs pretreated with itaconic acid, malonic acid or methylsuccinic acid.

2025-02-14 | GSE277689 | GEO

Itaconate modulates immune responses via inhibition of peroxiredoxin 5

Project description:Wild type and Irg1 knockout mouse bone marrow derived macrophages (BMDMs) were processed with a redox proteomics workflow and analyzed by LC-MS/MS with TMT based quantification.

2023-11-01 | MSV000093232 | MassIVE

Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation

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-1Î²-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

Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation

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.

2016-07-01 | GSE82043 | GEO

Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity

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

Itaconate enhances oncolytic virotherapy via multitarget inhibition of antiviral and inflammatory pathways

Project description:Itaconate enhances oncolytic virotherapy via multitarget inhibition of antiviral and inflammatory pathways

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Itaconate enhances oncolytic virotherapy via multitarget inhibition of antiviral and inflammatory pathways

Project description:4 octyl itaconate (4-OI) is a known anti-inflammatory chemical that activates Nrf2 signaling. Here, we are exploring the capacities of 4-OI to promote the spread of oncolytic Vesicular Stomatitis Virus (VSVd51M) in pLenti control kidney adenocarcinoma 786-O cell line and in Nrf2 knock out 786-O.

2023-06-15 | GSE232509 | GEO

Endogenously produced itaconate negatively regulates innate-driven cytokine production and drives global ubiquitination in human macrophages

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

Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition

Project description:Metabolic pathways fuel tumor progression and resistance to stress conditions including chemotherapeutic drugs, such as DNA damage response (DDR) inhibitors. Yet, significant gaps persist in how metabolic pathways confer resistance to DDR inhibition in cancer cells. Here, we employed a metabolism-focused CRISPR knockout screen and identified genetic vulnerabilities to DDR inhibitors. We unveiled Peroxiredoxin 1 (PRDX1) as a synthetic lethality partner with Ataxia Telangiectasia Mutated (ATM) kinase. Tumor cells depleted of PRDX1 displayed heightened sensitivity to ATM inhibition in vitro and in mice in a manner dependent on p53 status. Mechanistically, we discovered that the ribosomal protein RPL32 undergoes redox modification on active cysteine residues 91 and 96 upon ATM inhibition, promoting p53 stability and altered cell fitness. Our findings reveal a new pathway whereby RPL32 senses stress and induces p53 activation impairing tumor cell survival.

2025-01-19 | GSE272107 | GEO

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