DCAF1 regulates Treg senescence via the ROS axis during immunological aging
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA540226 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8983740_1.fastq.gz | Fastqsanger.gz | |||
| SRR8983740_2.fastq.gz | Fastqsanger.gz | |||
| SRR8983741_1.fastq.gz | Fastqsanger.gz | |||
| SRR8983741_2.fastq.gz | Fastqsanger.gz | |||
| SRR8983742_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 24 |
Similar Datasets
Project description:As a hallmark of immunological aging, low-grade, chronic inflammation with accumulation of effector memory T cells contributes to increased susceptibility to many aging-related diseases. While the proinflammatory state of aged T cells indicates a dysregulation of immune homeostasis, whether and how aging drives regulatory T cell (Treg) aging and alters Treg function are not fully understood owing to a lack of specific aging markers. Here, by a combination of cellular, molecular, and bioinformatic approaches, we discovered that Tregs senesce more severely than conventional T (Tconv) cells during aging. We found that Tregs from aged mice were less efficient than young Tregs in suppressing Tconv cell function in an inflammatory bowel disease model and in preventing Tconv cell aging in an irradiation-induced aging model. Furthermore, we revealed that DDB1- and CUL4-associated factor 1 (DCAF1) was downregulated in aged Tregs and was critical to restrain Treg aging via reactive oxygen species (ROS) regulated by glutathione-S-transferase P (GSTP1). Importantly, interfering with GSTP1 and ROS pathways reinvigorated the proliferation and function of aged Tregs. Therefore, our studies uncover an important role of the DCAF1/GSTP1/ROS axis in Treg senescence, which leads to uncontrolled inflammation and immunological aging.
| S-EPMC7598062 | biostudies-literature
Project description:Total RNA of regulatory T (Treg) cells and conventional CD4 T (Tconv) cells from young WT (2 months), aged WT (>18 months) and young Dcaf1-deficient mice was extracted and RNA-seq libraries were generated. Reads (32-45 Million reads per sample) were analyzed with Salmon software to align and quantify the transcript expression. R packages in Bioconductor, tximport and tximportData were used to aggregate transcript-level quantifications to the gene level, with the R package biomaRt for gene and transcripts mapping. The option "lengthScaledTPM" for countsFromAbundance in tximport was used to obtain the estimated counts at the gene level using abundance estimates scaled based on the average transcript length over samples and the library size. The option "lengthScaledTPM" for countsFromAbundance in tximport was used to obtain the estimated counts at the gene level using abundance estimates scaled based on the average transcript length over samples and the library size. For the differential expression (DE) analysis of RNA-seq data, gene-level count matrix was passed into by DESeq2 package as input directly from the tximport package. The normalized gene expression data was retrieved from DESeq2 analysis after regulated log (rlog) transformation (‘rlog’ in DESeq2). The z-score at gene-level average of normalized expression matrix was used to generate heatmap in Gene-E from Broad Institute (www.broadinstitute.org/ /GENE-E/). Gene Set Enrichment Analysis was performed using the Java application available from Broad Institute (www.broadinstitute.org/gsea/). Gene set databases including Hallmarks (h.all.v6.1.symbols.gmt) and KEGG (c2.cp.kegg.v6.1.symbols.gmt) from the Molecular Signatures Database (MSigDB) were used in the analysis. The aging-program gene set was from DEMAGALHAES_AGING_UP in MSigDB. One thousand gene set permutations were performed. FDR<0.05 was used for enriched terms, as is recommended when performing permutations by gene set.
2020-10-10 | GSE130419 | GEO
Project description:IKKα, one subunit of the IKK complex composed of IKKα, IKKβ, and IKKγ (NEMO), is essential for canonical and noncanonical NF-κB pathways involved in the development of lymphoid organs, leukocytes, immunity, and epithelial organs. Deletions of the CHUK locus that encodes IKKα significantly reduce survival for both KRAS-mutation lung adenocarcinoma (ADC) patients and mice, but the question of whether IKKα regulates immune responses remains unanswered. Here, we show that tumor-IKKα reduction elicits an immunosuppressive tumor-microenvironment associated with macrophage and Treg cell induction, which are maintained through elevated reactive oxygen species (ROS) and cytokines important for macrophage and Treg cell development in human and mouse lung ADCs. Enhanced macrophage-ROS and inflammatory cytokine signaling, mediated by tumor-cell IKKα reduction, enforces Treg cell differentiation via a ROS/TNFα/TNFR2/c-Rel pathway in CD4 T-cells. The blockage of each crucial step, including ROS, macrophages, Treg cells, and TNFα/c-Rel, impairs lung ADC development. To explore the molecular mechanism, we performed ChIP-Seq to check some important immunoregulatory genes including TNF, IL-23A CSF1, and CCL22 were regulated transcriptionally by IKKα. Therefore, IKKα serves as a specific surveillant that suppresses immunosuppressive responses and antagonizes lung carcinogenesis in humans and mice.
2022-01-31 | GSE132460 | GEO
Project description:Patients deficient in the guanine nucleotide exchange factor DOCK8 have decreased numbers and impaired in vitro function of T regulatory (Treg) cells and make autoantibodies, but seldom develop autoimmunity. We show that similarly, Dock8-/- mice have decreased numbers and impaired in vitrofunction of Treg cells, but do not develop autoimmunity. In contrast, mice with selective DOCK8 deficiency in Treg cells develop lymphoproliferation, autoantibodies, and gastrointestinal inflammation, despite normal percentage and in vitro function of Treg cells, suggesting that deficient T effector cell function might protect DOCK8 deficient patients from autoimmunity. We demonstrate that DOCK8 associates with STAT5 and is important for IL-2 driven STAT5 phosphorylation in Treg cells. DOCK8 localizes within the lamellar actin ring of the Treg cell immune synapse (IS). Dock8-/- Treg cells have abnormal TCR-driven actin dynamics, decreased adhesiveness, altered gene expression profile, an unstable IS with decreased recruitment of signaling molecules, and impaired transendocytosis of the co-stimulatory molecule CD86. These data suggest that DOCK8 enforces immunological tolerance by promoting IL-2 signaling, TCR-driven actin dynamics, and the IS in Treg cells.
2017-08-12 | GSE102577 | GEO
Project description:Leaf senescence is a highly coordinated and complicated process with the integration of numerous internal and environmental signals. Salicylic acid (SA) and reactive oxygen species (ROS) are two well-defined inducers of leaf senescence, whose contents progressively and inter-dependently increase during leaf senescence via a yet unknown mechanism. Here, we have characterized a newly identified positive regulator of leaf senescence, WRKY75, and demonstrated that knock-down or knock-out of WRKY75 delays, while over-expression of WRKY75 accelerates age-dependent leaf senescence. The WRKY75 transcription is induced by age, SA, H2O2, as well as multiple plant hormones. Meanwhile, WRKY75 is able to promote SA production by inducing the transcription of SA INDUCTION-DEFICIENT 2 (SID2), and suppress H2O2 scavenging partly by repressing the transcription of CATALASE 2 (CAT2). Genetic analysis reveals that the SID2 mutation or an increase of catalase activity rescues the precocious leaf senescence phenotype evoked by WRKY75 over-expression. Based on these results, we propose a “tripartite amplification loop” model in which WRKY75, SA and ROS undergo a gradual but self-sustained rise driven by three interlinked positive feedback regulations. This tripartite amplification loop provides a molecular framework connecting the upstream signals, such as age, ethylene, JA and ABA, to the downstream regulatory network executed by those SA-responsive and H2O2-responsive transcription factors during leaf senescence.
2017-11-07 | GSE102302 | GEO
Project description:The downstream events and target genes of p53 in senescence responses are not fully understood. Here, we report a novel function of the forkhead transcription factor Foxp3, a key player in mediating T cell inhibitory function, in p53-mediated cellular senescence. Overexpression of Foxp3 in mouse embryonic fibroblasts (MEFs) accelerates senescence, whereas Foxp3 knockdown leads to escape from p53-mediated senescence in p53-expressing MEFs. Consistently, Foxp3 expression resulted in the induction of senescence in epithelial cancer cells, including MCF7 and HCT116. Foxp3 overexpression also increased the intracellular levels of reactive oxygen species (ROS). The ROS inhibitor N-acetyl-L-cysteine rescued Foxp3 expression-induced senescence. Furthermore, the elevated ROS levels that accompanied Foxp3 overexpression were paralleled by an increase in p21 expression. Knockdown of p21 in Foxp3-expressing MEFs abrogated the Foxp3-dependent increase in ROS levels, indicating that Foxp3 acts through p21 induction and subsequent ROS elevation to trigger senescence. Collectively, these results suggest that Foxp3 is a downstream target of p53 that is sufficient to induce p21 expression and ROS production and is necessary for p53-mediated senescence. control and treated samples (human), young passage (p3) or old passage (p7) samples (mouse)
2015-08-13 | E-GEOD-71980 | biostudies-arrayexpress
Project description:Axitinib exposure triggers endothelial cells senescence through ROS accumulation and ATM activation
| PRJNA521866 | ENA
Project description:Kidney is a vital organ responsible for homeostasis in the body. To retard kidney aging is of great importance for maintaining body health. Whereas the therapeutic strategies targeting against kidney aging are not elucidated. Recent studies show mitochondrial dysfunction is critical for renal tubular cell senescence and kidney aging, however, the underlying mechanisms of mitochondrial dysfunction in kidney aging have not been demonstrated. Herein, we found calcium overload, and the mitochondrial calcium uniporter (MCU) was induced in renal tubular cells and aged kidney. To activate MCU not only triggered mitochondrial calcium overload, but also induced reactive oxygen species (ROS) production and cellular senescence and age-related kidney fibrosis. Inversely, to block MCU or chelate calcium diminished ROS generation, restored mitochondrial homeostasis, and retarded cell senescence and protected against kidney aging. These results demonstrate MCU plays a key role in promote renal tubular cell senescence, which provides a new insight on the therapeutic strategy for fighting against kidney aging.
2024-10-02 | GSE262514 | GEO
Project description:The downstream events and target genes of p53 in the process of senescence are not fully understood. Here, we report a novel function of the forkhead transcription factor Foxp3, which is a key player in mediating T cell inhibitory functions, in p53-mediated cellular senescence. The overexpression of Foxp3 in mouse embryonic fibroblasts (MEFs) accelerates senescence, whereas Foxp3 knockdown leads to escape from p53-mediated senescence in p53-expressing MEFs. Consistent with these results, Foxp3 expression resulted in the induction of senescence in epithelial cancer cells, including MCF7 and HCT116 cells. Foxp3 overexpression also increased the intracellular levels of reactive oxygen species (ROS). The ROS inhibitor N-acetyl-L-cysteine rescued cells from Foxp3-expression-induced senescence. Furthermore, the elevated ROS levels that accompanied Foxp3 overexpression were paralleled by an increase in p21 expression. Knockdown of p21 in Foxp3-expressing MEFs abrogated the Foxp3-dependent increase in ROS levels, indicating that Foxp3 acts through the induction of p21 and the subsequent ROS elevation to trigger senescence. Collectively, these results suggest that Foxp3 is a downstream target of p53 that is sufficient to induce p21 expression and ROS production and is necessary for p53-mediated senescence.
2015-08-13 | GSE71980 | GEO
Project description:Analysis of gene alternations during the process of senescence induced by human regulatory T cells at various time points. Total RNA obtained from isolated regulatory T (Treg) cell-treated responder CD8+ T cells compared to the untreated T cells
2012-10-03 | E-GEOD-38765 | biostudies-arrayexpress