Itaconate suppresses atherosclerosis by impeding inflammation through Nrf2 signaling
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ABSTRACT:
PROVIDER: PRJNA987560 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25023544_1.fastq.gz | Fastqsanger.gz | |||
| SRR25023544_2.fastq.gz | Fastqsanger.gz | |||
| SRR25023545_1.fastq.gz | Fastqsanger.gz | |||
| SRR25023545_2.fastq.gz | Fastqsanger.gz | |||
| SRR25023546_1.fastq.gz | Fastqsanger.gz |
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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:Metabolic regulation recently emerged as a novel powerful principle guiding immune responses. The natural metabolite itaconate and its membrane permeable derivative dimethyl itaconate (DI) were recently shown to selectively inhibit a subset of cytokines during macrophage activation, yet the precise mechanism of this effect remained unclear. We show here that itaconate/DI react with glutathione and subsequently induce both Nrf2-dependent and Nrf2-independent stress responses. We find that the striking selectivity of DI action stems from the inhibitory effects of electrophilic stress on IKBZ protein translation, leading to the inhibition of only the secondary wave of NF-KB signaling. We find that IKBZ regulation occurs in an Nrf2-independent manner, and identify ATF3 as a key mediator of the immunosuppression.
2018-02-25 | MSV000082101 | MassIVE
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:Nrf2 (NF-E2-related factor-2) transcription factor regulates oxidative/xenobiotic stress response and also represses inflammation. However, the mechanisms how Nrf2 alleviates inflammation are still unclear. Here, we demonstrate that Nrf2 interferes with lipopolysaccharide-induced transcriptional upregulation of proinflammatory cytokines, including IL-6 and IL-1β. ChIP-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes in macrophages and inhibits RNA Pol II recruitment. Further, we found that Nrf2-mediated inhibition is independent of the Nrf2 binding motif and reactive oxygen species level. Murine inflammatory models further demonstrated that Nrf2 interferes with IL6 induction and inflammatory phenotypes in vivo. Thus, contrary to the widely accepted view that Nrf2 suppresses inflammation through redox control, we demonstrate here that Nrf2 opposes transcriptional upregulation of proinflammatory cytokine genes. This study identifies Nrf2 as the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach. Gene expression in BMDMs obtained from wild-type and Keap1-CKO mice. In Keap1-CKO (Keap1 flox/flox::LysM-Cre) BMDMs, Nrf2 transcription factor is activated due to Keap1-deficiency. BMDMs were obtained by a culture of bone marrow cells in the presence of M-CSF for7 days. M1-activated BMDMs were obtained by stimulation with LPS and IFNg for 6 hours, while M2-activated BMDMs were obtained by a stimulation with IL-4 for 6 hours. Two independent BMDM cultures were performed, and each experiment contains samples obtained from one wild-type and one Keap1-CKO mice, respectively.
2016-05-12 | E-GEOD-71263 | biostudies-arrayexpress
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. Deletion of Acod1 in myeloid cells exacerbated inflammation and atherosclerosis in vivo and resulted in an elevated frequency of a specific subset of M1-polarized proinflammatory macrophages in the atherosclerotic aorta. Importantly, Acod1 levels were inversely correlated with clinical occlusion in atherosclerotic human aorta specimens. Treating mice with the itaconate derivative 4-octyl itaconate attenuated inflammation and atherosclerosis induced by high cholesterol. Mechanistically, we found that the antioxidant transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), was required for itaconate to suppress macrophage activation induced by oxidized lipids in vitro and to decrease atherosclerotic lesion areas in vivo. Overall, our work shows that itaconate suppresses atherogenesis by inducing Nrf2-dependent inhibition of proinflammatory responses in macrophages. Activation of the itaconate pathway may represent an important approach to treat atherosclerosis.
| S-EPMC10849764 | biostudies-literature
Project description:The transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is activated by the metabolite itaconate during metabolic reprogramming. Activated Nrf2 then dampens the release of pro-inflammatory cytokines and type I IFNs in response to toll-like receptor stimulation. If and how Nrf2 affects cytosolic antiviral sensing and whether this occurs during metabolic reprogramming is currently not known. Here, we show that Nrf2 is a negative regulator of the adaptor molecule STimulator of INterferon Genes (STING), which signals downstream of the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS). The regulation of STING by Nrf2 was inducible by the metabolite itaconate, specific to human cells, and sufficient to decrease the responsiveness to STING agonists and to increase the susceptibility to infection with DNA viruses. Mechanistically, Nrf2 regulated STING expression post-transcriptionally by increasing STING mRNA stability. Lastly, treatment with itaconate or with the chemical Nrf2 inducer sulforaphane repressed STING expression and the release of type I IFNs in cells from patients with the STING dependent interferonopathy SAVI. With this report we identify Nrf2 as an important regulator of cGAS-STING signaling pathway and link metabolic reprogramming to control of cytosolic DNA sensing.
2018-05-01 | GSE113519 | GEO
Project description:Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discovered SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identified a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitized tumors to ferroptosis, curbed tumor progression, and bolstered ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target and disease indication for treating SLC13A3+cancer.
2024-09-19 | GSE268205 | GEO
Project description:Endothelial IGFBP6 Suppresses Vascular Inflammation and Atherosclerosis
| PRJNA1104204 | ENA
Project description:Nrf2 (NF-E2-related factor-2) transcription factor regulates oxidative/xenobiotic stress response and also represses inflammation. However, the mechanisms how Nrf2 alleviates inflammation are still unclear. Here, we demonstrate that Nrf2 interferes with lipopolysaccharide-induced transcriptional upregulation of proinflammatory cytokines, including IL-6 and IL-1β. ChIP-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes in macrophages and inhibits RNA Pol II recruitment. Further, we found that Nrf2-mediated inhibition is independent of the Nrf2 binding motif and reactive oxygen species level. Murine inflammatory models further demonstrated that Nrf2 interferes with IL6 induction and inflammatory phenotypes in vivo. Thus, contrary to the widely accepted view that Nrf2 suppresses inflammation through redox control, we demonstrate here that Nrf2 opposes transcriptional upregulation of proinflammatory cytokine genes. This study identifies Nrf2 as the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach.
2016-05-12 | GSE71263 | GEO
Project description:Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discovered SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identified a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitized tumors to ferroptosis, curbed tumor progression, and bolstered ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target and disease indication for treating SLC13A3+cancer.
2024-09-19 | GSE268293 | GEO