The PRAK-NRF2 axis promotes the differentiation of Th17 cells by mediating the redox homeostasis and glycolysis
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ABSTRACT:
PROVIDER: PRJNA956534 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24196206.fastq.gz | Fastqsanger.gz | |||
| SRR24196207.fastq.gz | Fastqsanger.gz | |||
| SRR24196208.fastq.gz | Fastqsanger.gz | |||
| SRR24196209.fastq.gz | Fastqsanger.gz |
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Project description:To investigate the function of PRAK in the regulation of Th17 differentiation, we polarized wild type and PRAK-KO naïve CD4+ T cells into Th17 cells for 72h in vitro. We then collected two types of polarized Th17 cells and performed gene expression profiling analysis using data obtained from RNA-seq.
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Project description:The aim of this study is to investigate a role of glycolysis in transcriptional programing of Th17 cells during differentiation. Naïve CD4 T cells were differentiated towards Th17 cells with or without a mild inhibition of glycolysis, and transcriptome signature was analyzed. We found about 200 transcripts were differentially regulated. Further pathway analysis suggested that glycolysis controls genes associated with IL-2/STAT5 signaling during Th17 differentiation. Inhibition of glycolysis resulted in enrichment of genes associated with translational processes and Th17 signature genes.
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Project description:Oxidative stress is a key feature in both chronic inflammation and cancer. P38 regulated/activated protein kinase (PRAK) deficiency can cause functional disorders in neutrophils and macrophages under high oxidative stress, but the precise mechanisms by which PRAK regulates reactive oxygen species (ROS) elimination and its potential impact on CD4+ T helper subset function are unclear. The present study reveals that the PRAK-NF-E2-related factor 2(NRF2) axis is essential for maintaining the intracellular redox homeostasis of T helper 17(Th17) cells, thereby promoting Th17 cell differentiation and antitumor effects. Through mechanistic analysis, we identify NRF2 as a novel protein substrate of PRAK and find that PRAK enhances the stability of the NRF2 protein through phosphorylation NRF2 Serine(S) 558 independent of protein ubiquitination. High accumulation of cellular ROS caused by loss of PRAK disrupts both glycolysis and PKM2-dependent phosphorylation of STAT3, which subsequently impairs the differentiation of Th17 cells. As a result, Prak knockout (KO) mice display significant resistance to experimental autoimmune encephalomyelitis (EAE) but impaired antitumor immunity in a MC38 tumor model. This work reveals that the PRAK-NRF2-mediated antioxidant pathway is a metabolic checkpoint that controls Th17-cell glycolysis and differentiation. Targeting PRAK is a promising strategy for maintaining an active ROS scavenging system and may lead to potent Th17 cell antitumor immunity.
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Project description:Glycolysis is a master regulator of cellular energy, synthesis and redox regulation, however the mechanisms that underlie the responses to and regulation of changing glucose metabolism are incompletely understood. The NRF2-antioxidant response element (ARE) pathway serves as a central regulator of cellular stress by sensing and eliminating 2 chemically reactive species in the cell. A phenotypic high-throughput chemical screen for novel activators of NRF2 signaling identified an inhibitor of the glycolytic enzyme PGK1. Metabolomic and proteomic profiling experiments revealed that inhibition of PGK1 results in the accumulation of central glycolytic intermediates, as well as the reactive dicarbonyl metabolite methylglyoxal (MGx). MGx selectively modifies reactive residues on KEAP1, resulting in the formation of a covalent KEAP1 homodimer, accumulation of NRF2 and activation of the NRF2 transcriptional program. Proteomic and NMR experiments verified that KEAP1 homodimerization is mediated by a novel post-translational modification, termed MICA, formed by the reaction of methylglyoxal with proximal cysteine and arginine residues. The identified PGK1 inhibitor series was found to be efficacious in a NRF2-dependent mouse model of UV-damage, demonstrating that activation of KEAP1- NRF2 signaling through this mechanism is physiologically relevant. Together, these results demonstrate the existence of direct inter-pathway communication between glycolysis and the KEAP1-NRF2 transcriptional program, which is mediated by a reactive metaboliteinduced post-translational modification (rmPTM). In addition, they provide new insight into metabolic regulation of cell stress response, and a potential therapeutic axis for controlling the cytoprotective antioxidant response in numerous human diseases.
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Project description:It is well known that some pathogenic cells have enhanced glycolysis, the regulatory network leading to increased glycolysis are not well characterized. Here, we show that CNS-infiltrated pathogenic TH17 cells from diseased mice specifically upregulate glycolytic pathway genes compared to homeostatic intestinal TH17 cells. Bioenergetic assay and metabolomics analyses indicate that in vitro derived pathogenic TH17 cells are highly glycolytic compared to nonpathogenic TH17 cells. Chromatin landscape analyses demonstrate TH17 cells in vivo show distinct chromatin states, and pathogenic TH17 cells show enhanced chromatin accessibility at glycolytic genes with NF-kB binding sites. Mechanistic studies reveal that miR-21 targets the E3 ubiquitin ligase Peli1-c-Rel pathway to promote glucose metabolism of pathogenic TH17 cells. Therapeutic targeting c-Rel-mediated glycolysis in pathogenic TH17 cells represses autoimmune diseases. These findings extend our understanding of the regulation TH17 cell glycolysis in vivo and provide insights for future therapeutic intervention to TH17 cell mediated autoimmune diseases.
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Project description:Persistent antigen stimulation exposes CD8+ T cells to various metabolic stresses and induces a dysfunctional state termed T-cell exhaustion. Exhausted CD8+ T cells are continuously replenished by a recently discovered self-renewing stem-like CD8+ T-cell subset, which maintains long-term immunity and provides proliferative burst in response to immunotherapies. Although the redox system plays an important role in regulating T-cell activation, how cellular redox affects the differentiation of stem-like and exhausted CD8+ T cells is incompletely understood. Here, we showed that both antigen stimulation and terminal differentiation reduced mitochondrial oxidation and reactive oxygen species (ROS) in exhausted CD8+ T cells, which displayed a chromatin state primed for regulation by the redox sensing KEAP1-NRF2 pathway. During chronic viral infection, KEAP1 promoted expansion of antiviral CD8+ T cells and facilitated their differentiation into the stem-like subset in a cell autonomous manner. In addition, KEAP1 was required for establishing proper transcriptional programs of stem-like and exhausted CD8+ T cells. Mechanistically, KEAP1 maintained oxidation by upregulating genes involved in mitochondrial oxidation and repressing NRF2-driven transcription of antioxidant pathways. Deleting KEAP1 binding domain in NRF2 released NRF2 from regulation by KEAP1, impaired expansion and stemness of CD8+ T cells, and dysregulated multiple metabolic pathways including redox pathways. Thus, our study revealed a novel role of the redox pathway in regulating the molecular program and differentiation of stem-like and exhausted CD8+ T cells during chronic antigen stimulation.
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Project description:Due to the limited expression of several antioxidant enzymes, β-cells are highly vulnerable to high ROS levels, which can lead to the reduction of functional β-cell mass. During early postnatal ages, both human and rodent β-cells go through a burst of proliferation that quickly declines with age. Here we discovered that the expression of the master antioxidant regulator, Nrf2, is increased during this postnatal burst of β-cell proliferation in humans. Additionally, data from β-cell specific Nrf2 deletion in mice demonstrated that Nrf2 is required for β-cell proliferation, β-cell survival, β-cell identity and β-cell mass expansion at early stages of life. Daily administration of antioxidant NAC to newborn mice showed that Nrf2 mechanism of action strongly relies on maintaining normal redox balance. Interestingly, RNAseq of islets isolated from β-cell specific Nrf2 deleted mice suggests that Nrf2 regulates neonatal β-cell proliferation by promoting mitochondrial ATP synthesis. Our study highlights Nrf2 as an essential transcription factor for maintaining redox balance as well as mitochondrial biogenesis and function to support neonatal β-cell growth and for maintaining functional β-cell mass in adulthood under metabolic stress.
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Project description:Transcriptional profile of Th17 cells: The role of glycolysis
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Project description:To evaluate whether NAD+-boosting modulates adaptive immunity, primary CD4+ T cells from healthy control and psoriasis subjects were exposed to vehicle or nicotinamide riboside (NR) supplementation. NR blunts IFNg and IL-17 secretion with greater effects on TH17 polarization. RNA-seq analysis implicates NR blunting of sequestosome 1 (SQSTM1/p62)-coupled oxidative stress. NR administration increases SQSTM1 and reduces reactive oxygen species (ROS) levels. Furthermore NR activates NRF2, and genetic knockdown of NRF2 and of the NRF2-dependent gene, SQSTM1 diminish NR amelioratory effects. Metabolomic analysis identify that NAD+-boosting increases arginine and fumarate biosynthesis and genetic knockdown of argininosuccinate lyase ameliorates NR-effects on IL-17 production. Hence, NR via amino acid metabolites orchestrate NRF2 activation, augments CD4+ T cell antioxidant defenses and attenuates TH17 responsiveness. Oral NR supplementation in healthy volunteers similarly increase serum arginine, SQSTM1 and antioxidant enzyme gene expression and blunts TH17 immune responsiveness, supporting evaluation of NAD+-boosting in CD4+ T cell linked inflammation.
2023-07-18 | GSE237555 | GEO
Project description:To evaluate whether NAD+-boosting modulates adaptive immunity, primary CD4+ T cells from healthy control and psoriasis subjects were exposed to vehicle or nicotinamide riboside (NR) supplementation. NR blunts IFNg and IL-17 secretion with greater effects on TH17 polarization. RNA-seq analysis implicates NR blunting of sequestosome 1 (SQSTM1/p62)-coupled oxidative stress. NR administration increases SQSTM1 and reduces reactive oxygen species (ROS) levels. Furthermore NR activates NRF2, and genetic knockdown of NRF2 and of the NRF2-dependent gene, SQSTM1 diminish NR amelioratory effects. Metabolomic analysis identify that NAD+-boosting increases arginine and fumarate biosynthesis and genetic knockdown of argininosuccinate lyase ameliorates NR-effects on IL-17 production. Hence, NR via amino acid metabolites orchestrate NRF2 activation, augments CD4+ T cell antioxidant defenses and attenuates TH17 responsiveness. Oral NR supplementation in healthy volunteers similarly increase serum arginine, SQSTM1 and antioxidant enzyme gene expression and blunts TH17 immune responsiveness, supporting evaluation of NAD+-boosting in CD4+ T cell linked inflammation.
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