Expression data from CD4+CD25- T cells of VAVcreKeapfl/fl mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE325439 | GEO | 2026/03/24
REPOSITORIES: GEO
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Project description:The transcription factor Nrf2 regulates oxidative stress responses. The specific role played by Nrf2 in regulatory T cells (Treg), the central regulators of immune homeostasis, is unclear. We used microarrays to detail the global programme of gene expression in CD4+CD25+ T cells of VAVcreKeapfl/fl mice
2021-02-20 | GSE110874 | GEO
Project description:Upon antigenic stimulation, CD4+T-cells undergo clonal expansion elevating their bioenergetic demands and utilization of nutrients like glucose and glutamine The nuclear factor erythroid 2-related factor2 (Nrf2) is a well-known regulator of oxidative stress, but its involvement in modulating the metabolism of CD4+T-cells remain unexplored. We report that Nrf2 protein levels are temporally regulated in activated CD4+T-cells, with elevated expression during early activation followed by a decline. T-cell-specific constitutive activation of Nrf2 by deletion of its regulator Keap1, enhances early activation and IL-2 secretion, upregulates TCR-signaling, and increases activation-driven expansion of CD4+T-cells. Metabolically, high Nr2 alters glucose metabolism and promotes glutamine metabolism via glutaminolysis to support increased CD4+T-cell proliferation. Mechanistically, elevated Nrf2 activity in activated CD4+T-cells leads to increased chromatin accessibility and proliferation-associated gene expression. In summary, we elucidate the role of Nrf2 beyond traditional antioxidation in modulating the activation-driven expansion of CD4+T-cells by influencing their nutrient metabolism.
2025-07-15 | GSE292639 | GEO
Project description:Upon antigenic stimulation, CD4+T-cells undergo clonal expansion elevating their bioenergetic demands and utilization of nutrients like glucose and glutamine The nuclear factor erythroid 2-related factor2 (Nrf2) is a well-known regulator of oxidative stress, but its involvement in modulating the metabolism of CD4+T-cells remain unexplored. We report that Nrf2 protein levels are temporally regulated in activated CD4+T-cells, with elevated expression during early activation followed by a decline. T-cell-specific constitutive activation of Nrf2 by deletion of its regulator Keap1, enhances early activation and IL-2 secretion, upregulates TCR-signaling, and increases activation-driven expansion of CD4+T-cells. Metabolically, high Nr2 alters glucose metabolism and promotes glutamine metabolism via glutaminolysis to support increased CD4+T-cell proliferation. Mechanistically, elevated Nrf2 activity in activated CD4+T-cells leads to increased chromatin accessibility and proliferation-associated gene expression. In summary, we elucidate the role of Nrf2 beyond traditional antioxidation in modulating the activation-driven expansion of CD4+T-cells by influencing their nutrient metabolism.
2025-07-15 | GSE292638 | GEO
Project description:The transcription factor NF-E2-related factor 2 (Nrf2) induces cytoprotective genes, but has also been linked to the regulation of hepatic energy metabolism. In order to assess the pharmacological potential of hepatic Nrf2 activation in metabolic disease, Nrf2 was activated over 8 weeks in mice on Western diet using two different siRNAs against kelch-like ECH-associated protein 1 (Keap1), the inhibitory protein of Nrf2. Whole genome expression analysis followed by pathway analysis demonstrated that the suppression of Keap1 expression induced genes that are involved in anti-oxidative stress defense and biotransformation, pathways proving the activation of Nrf2 by the siRNAs against Keap1. The expression of neither fatty acid- nor carbohydrate-handling proteins was regulated by the suppression of Keap1. Metabolic profiling of the animals did also not show effects on plasma and hepatic lipids, energy expenditure or glucose tolerance by the activation of Nrf2. The data indicate that hepatic Nrf2 is not a major regulator of intermediary metabolism in mice. Gene expression profile of mouse liver samples from 8-week-old male C57BL6/J mice (N=24) treated with liver-selective Keap1-specific siRNA (group 1: siKeap1-1, N=8; group 2: siKeap1-2, N=8) or unspecific scrambled control siRNA (group 3: siControl, N=8)
2016-09-01 | E-GEOD-80956 | biostudies-arrayexpress
Project description:The activation of the transcription factor NF-E2-related factor 2 (Nrf2) maintains cellular homeostasis in response to oxidative stress by the regulation of multiple cytoprotective genes. Without stressors the activity of Nrf2 is inhibited by its interaction with the kelch-like ECH-associated protein 1 (Keap1). Here, we describe RA839, a small molecule that binds non-covalently to the Nrf2-interacting kelch domain of Keap1 with a Kd of approximately 6 µM, as demonstrated by X-ray co-crystallization and isothermal titration calorimetry. Whole-genome DNA arrays showed that at 10 µM RA839 significantly regulated 105 genes in bone marrow-derived macrophages. Canonical pathway mapping of these genes revealed an activation of pathways linked with Nrf2 signalling. These pathways were also activated after the activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only two genes in Nrf2 knockout macrophages. Similar to the activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound CDDO-Me, RA839 prevented the induction of both inducible nitric oxide synthase expression and nitric oxide release in response to lipopolysaccharides in macrophages. In mice RA839 acutely induced Nrf2-target gene expression in liver. RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the biology of Nrf2. Gene expression profile of bone marrow derived murine macrophages (BMDM) from Nrf2+/+ or Nrf2-/- mice treated with RA838, siKeap1-1 or siKeap1-2 were compared to untreated DMSO control or siControl. Four biological replicates were used for each sample group.
2015-10-31 | E-GEOD-71695 | biostudies-arrayexpress
Project description:Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct hepatic gene expression profiles between Keap1 knockout and triterpenoid treated mice; Loss of Nrf2 signaling increases susceptibility to acute toxicity, inflammation, and carcinogenesis in mice due to the inability to mount adaptive responses. By contrast, disruption of Keap1 (a cytoplasmic modifier of Nrf2 turnover) protects against these stresses in mice; although dominant negative mutations in Keap1 have been identified recently in some human cancers. Global characterization of Nrf2 activation is important to exploit this pathway for chemoprevention in healthy, yet at-risk individuals and also to elucidate the consequences of hijacking the pathway in Keap1-mutant human cancers. This analysis also enables a global characterization of the pharmacodynamic action of CDDO-Im at a low dose that is relevant to chemoprevention. Experiment Overall Design: Liver-targeted conditional Keap1-null (CKO) mice provide a model of genetic activation of Nrf2 signaling. By coupling global gene expression analysis of CKO mice with analysis of pharmacologic activation using the synthetic oleanane triterpenoid CDDO-Im, we are able to gain insight into pathways affected by Nrf2 activation. CDDO-Im is an extremely potent activator of Nrf2 signaling. CKO mice were used to identify genes modulated by genetic activation of Nrf2 signaling. The CKO response was compared to hepatic global gene expression changes in wild-type mice treated with CDDO-Im at a maximal Nrf2 activating dose. n=3/group, male 9 week old mice were used. Mice were treated with a single dose of vehicle (10% Cremophor-EL, 10% DMSO, and PBS) or 30 umol CDDO-Im/kg body weight by gavage and sacrificed 6 h later.
2009-05-11 | E-GEOD-15633 | biostudies-arrayexpress
Project description:NF-E2-related factor-2 (Nrf2) regulates the cellular response to oxidative/electrophilic stresses, and loss of Keap1 increases the Nrf2 protein level. As Keap1-null mice die of esophageal hyperkeratosis, whole-body phenotypes of Nrf2 hyperactivation in adult animals remain to be delineated. Here we show that deleting esophageal Nrf2 in Keap1-null mice the mice survive until adulthood, but develop polyuria with low osmolality and bilateral hydronephrosis. This novel phenotype is to be attributable to defects in water reabsorption caused by a reduction in the level of the aquaporin 2 (AQP2) channel in the kidney. In line, renal tubular deletion of Keap1 generates symptoms of nephrogenic diabetes insipidus, demonstrating that Nrf2 activation in developing tubular cells causes a water reabsorption defect. The rescue of mice from the lethal first hit of Keap1 ablation serves as a useful tool to study novel functions of Nrf2.
2017-06-12 | GSE84780 | GEO
Project description:Background & Aims: Inflammation in chronic liver diseases induces oxidative stress and thus may contribute to progression of liver injury, fibrosis, and carcinogenesis. The KEAP1/NRF2 axis is a major regulator of cellular redox balance. In the present study, we investigated whether the KEAP1/NRF2 system is involved in liver disease progression in human and mice. Methods: The clinical relevance of oxidative stress was investigated in a well-characterized cohort of NAFLD patients (n=63) by liver RNA sequencing and correlated with histological and clinical parameters. For functional analysis hepatocyte-specific NEMO knock-out (NEMO∆hepa) mice were crossed with hepatocyte-specific KEAP1 knock-out (KEAP1∆hepa) mice. Results: Immunohistochemical analysis of human liver sections showed increased oxidative stress and high NRF2 expression in patients with chronic liver disease. RNA sequencing of liver samples in a human pediatric NAFLD cohort revealed a significant increase of NRF2 activation correlating with the grade of inflammation, but not with the grade of steatosis, which could be confirmed in a second adult NASH cohort. In mice, microarray analysis revealed that KEAP1 deletion induces NRF2 target genes involved in glutathione metabolism and xenobiotic stress (e.g., Nqo1). Furthermore, deficiency of one of the most important antioxidants, glutathione (GSH), in NEMO∆hepa livers was rescued after deleting KEAP1. As a consequence, NEMO∆hepa/KEAP1∆hepa livers showed reduced apoptosis compared to NEMO∆hepa livers as well as a dramatic downregulation of genes involved in cell cycle regulation and DNA replication. Consequently, NEMO∆hepa/KEAP1∆hepa compared to NEMOΔhepa livers displayed decreased fibrogenesis, lower tumor incidence, reduced tumor number, and decreased tumor size. Conclusions: NRF2 activation in NASH patients correlates with the grade of inflammation, but not steatosis. Functional analysis in mice demonstrated that NRF2 activation in chronic liver disease is protective by ameliorating fibrogenesis, initiation and progression of hepatocellular carcinogenesis.
2021-05-26 | GSE156838 | GEO
Project description:Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that induces a battery of cytoprotective genes in response to oxidative/electrophilic stress. Kelch-like ECH associating protein 1 (Keap1) sequesters Nrf2 in the cytosol. The purpose of this study was to investigate the role of Nrf2 in regulating the mRNA of genes encoding drug metabolizing enzymes and xenobiotic transporters. Microarray analysis was performed in livers of Nrf2-null, wild-type, Keap1-knockdown mice with increased Nrf2 activation, and Keap1-hepatocyte knockout mice with maximum Nrf2 activation. In general, Nrf2 did not have a marked effect on uptake transporters, but the mRNAs of organic anion transporting polypeptide 1a1, sodium taurocholate cotransporting polypeptide, and organic anion transporter 2 were decreased with Nrf2 activation. The effect of Nrf2 on cytochrome P450 (Cyp) genes was minimal, with only Cyp2a5, Cyp2c50, Cyp2c54, and Cyp2g1 increased, and Cyp2u1 decreased with enhanced Nrf2 activation. However, Nrf2 increased mRNA of many other phase-I enzymes, such as aldo-keto reductases, carbonyl reductases, and aldehyde dehydrogenase 1. Many genes involved in phase-II drug metabolism were induced by Nrf2, including glutathione S -transferases, UDP- glucuronosyltransferases, and UDP-glucuronic acid synthesis enzymes. Efflux transporters, such as multidrug resistance-associated proteins, breast cancer resistant protein, as well as ATP-binding cassette g5 and g8 were induced by Nrf2. In conclusion, Nrf2 markedly alters hepatic mRNA of a large number of drug metabolizing enzymes and xenobiotic transporters, and thus Nrf2 plays a central role in xenobiotic metabolism and detoxification. We used microarrays to detail the global programme of gene expression in response to Nrf2 activation and identified distinct classes of up- and down-regulated genes. process. Gene expression in livers of Nrf2-null, WT, Keap1-KD, and Keap1-HKO mice was determined using Affymetrix Mouse 430.20 arrays by the KUMC Microarray Core Facility. Biological cRNA replicates (n=3) of each genotype were hybridized to an individual array.
2014-02-18 | E-GEOD-55001 | biostudies-arrayexpress
Project description:Clinical observations have revealed that NRF2 hyperactivation in cancer cells is often associated with immune suppression in the tumor microenvironment. However, it remains unclear whether NRF2 hyperactivation directly reduces immune cell infiltration into tumors. To address this question, we established a syngeneic mouse model using transplantation of 3LL lung cancer-derived cells with either NRF2 hyperactivation via Keap1 gene deletion or concomitant Keap1-Nrf2 gene deletion. A series of flowcytometry, histological analysis, and comprehensive gene expression profiling demonstrated that immune cell infiltration was significantly reduced in KEAP1-deleted tumors, with marked decrease in CD45-positive cells, particularly myeloid and monocytic populations. In contrast, concomitant deletion of NRF2 restored immune cell infiltration in the KEAP1-deleted tumors. These findings provide convincing lines of evidence that NRF2 activation in cancer cells suppresses immune cell infiltration into tumors. Our study sheds light on the mechanistic basis by which NRF2 activation contributes to cancer malignancy.
2025-08-20 | GSE299332 | GEO