Effects of Irg1-itaconate or Hemin on gene expression in macrophages [RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA915639 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22890377.fastq.gz | Fastqsanger.gz | |||
| SRR22890378.fastq.gz | Fastqsanger.gz | |||
| SRR22890379.fastq.gz | Fastqsanger.gz | |||
| SRR22890380.fastq.gz | Fastqsanger.gz | |||
| SRR22890381.fastq.gz | Fastqsanger.gz |
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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:To investigate the role of Irg1-itacaonate on Nrf2-transcripting genes in macrophages, RAW264.7 cells were cultured and were treated 120 μM 4-octyl itaconate (4-OI) or Vehicle for 8 h. We then performed ChIP-seq analysis from 4-OI or vehicle treated RAW264.7 cells using Nrf2 or IgG antibodies.
2024-06-28 | GSE221843 | 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: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: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: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:Immune-responsive gene 1 (IRG1) is a mitochondrial aconitate decarboxylase and can produce the immunomodulatory metabolite itaconic acid (ITA). However, its role in modulating the function of tumor-associated macrophages (TAMs) remains elusive. Here, we show that IRG1 is expressed in TAMs in human tumors and mouse models of cancer. Tumor cells induce Irg1 expression in macrophages which dampens the inflammatory response and restricts M1-like TAM polarization. In contrast, Irg1-deficent macrophages acquire more proinflammatory M1-like features, promote immunogenic antigen presentation, and enhance cytotoxic T cell infiltration into tumor sites. Consequently, Irg1 deficiency suppresses the growth of mouse syngeneic tumors, including melanoma, colorectal cancer, breast cancer, and pancreatic cancer. Irg1-deficient macrophages not only dictate the tumoricidal effect but enhance the efficacy of anti-PD(L)1 immunotherapy. In conclusion, our data identify IRG1 as a myeloid immune check point gene and foster the development of genetic or pharmacologic targeting of IRG1 for skewing macrophages toward an anti-tumor phenotype to treat a broad spectrum of cancer.
2023-05-01 | GSE210845 | GEO
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
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: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