Fasting-Induced FOXO4 Blunts Human CD4+ T Helper Cell Responsiveness
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA693349 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13486800_1.fastq.gz | Fastqsanger.gz | |||
| SRR13486800_2.fastq.gz | Fastqsanger.gz | |||
| SRR13486801_1.fastq.gz | Fastqsanger.gz | |||
| SRR13486801_2.fastq.gz | Fastqsanger.gz | |||
| SRR13486802_1.fastq.gz | Fastqsanger.gz |
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Project description:Intermittent fasting blunts inflammation in asthma1 and rheumatoid arthritis2, suggesting that fasting may be exploited as an immune-modulatory intervention. However, the mechanisms underpinning the anti-inflammatory effects of fasting are poorly characterized3-5. Here, we show that fasting in humans is sufficient to blunt CD4+ T helper cell responsiveness. RNA sequencing and flow cytometry immunophenotyping of peripheral blood mononuclear cells from volunteers subjected to overnight or 24-h fasting and 3 h of refeeding suggest that fasting blunts CD4+ T helper cell activation and differentiation. Transcriptomic analysis reveals that longer fasting has a more robust effect on CD4+ T-cell biology. Through bioinformatics analyses, we identify the transcription factor FOXO4 and its canonical target FK506-binding protein 5 (FKBP5) as a potential fasting-responsive regulatory axis. Genetic gain- or loss-of-function of FOXO4 and FKBP5 is sufficient to modulate TH1 and TH17 cytokine production. Moreover, we find that fasting-induced or genetic overexpression of FOXO4 and FKBP5 is sufficient to downregulate mammalian target of rapamycin complex 1 signalling and suppress signal transducer and activator of transcription 1/3 activation. Our results identify FOXO4-FKBP5 as a new fasting-induced, signal transducer and activator of transcription-mediated regulatory pathway to blunt human CD4+ T helper cell responsiveness.
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Project description:AKT1 is a serine/threonine kinase implicated in fetal, placental, and postnatal growth. In this study, we investigated roles for AKT1 in placental development using a genome-edited/loss-of-function rat model. Both heterozygous and homozygous Akt1 mutant rats were viable and fertile. Disruption of AKT1 resulted in placental, fetal, and postnatal growth restriction. Akt1 null placentas showed deficits in both junctional zone and labyrinth zone size and their ability to adapt to a physiological stressor. Robust differences in the transcriptome of wild type versus Akt1 null junctional zones were identified. Among the differentially expressed junctional zone transcripts was forkhead box O4 (Foxo4), which encodes a transcription factor and known AKT substrate. FOXO4 expression was prominent in the junctional zone and invasive trophoblast cells of the rat placentation site and enhanced following rat TS cell differentiation. Foxo4 gene disruption using genome-editing resulted in placentomegaly, including an enlarged junctional zone. AKT1 and FOXO4 regulate the expression of many of the same transcripts expressed by trophoblast cells; however, in opposite directions. In summary, we have identified AKT1 and FOXO4 as part of a regulatory network controlling hemochorial placenta development.
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Project description:AKT1 is a serine/threonine kinase implicated in fetal, placental, and postnatal growth. In this study, we investigated roles for AKT1 in placental development using a genome-edited/loss-of-function rat model. Both heterozygous and homozygous Akt1 mutant rats were viable and fertile. Disruption of AKT1 resulted in placental, fetal, and postnatal growth restriction. Akt1 null placentas showed deficits in both junctional zone and labyrinth zone size and their ability to adapt to a physiological stressor. Robust differences in the transcriptome of wild type versus Akt1 null junctional zones were identified. Among the differentially expressed junctional zone transcripts was forkhead box O4 (Foxo4), which encodes a transcription factor and known AKT substrate. FOXO4 expression was prominent in the junctional zone and invasive trophoblast cells of the rat placentation site and enhanced following rat TS cell differentiation. Foxo4 gene disruption using genome-editing resulted in placentomegaly, including an enlarged junctional zone. AKT1 and FOXO4 regulate the expression of many of the same transcripts expressed by trophoblast cells; however, in opposite directions. In summary, we have identified AKT1 and FOXO4 as part of a regulatory network controlling hemochorial placenta development.
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Project description:Analysis of mechano-regulation of tenocyte metabolism at gene expression level. The hypothesis tested in the present study was that cyclic tensile strain influence the balance of anabolism/catabolism of tenocytes. Forkhead box O (FoxO) proteins are a family of transcription factors implicated in many biological processes including immune regulation. In this study, we found that mice null for Foxo4, a member of the FoxO family, are more susceptible to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis than wild type controls. To understand the mechanism of elevated colitis susceptibility and the nature of the TNBS-induced colitis in Foxo4-null mice, we performed microarray analysis with mucosal cDNA samples from large intestines of untreated, ethanol and TNBS-treated wild type and Foxo4 KO mice. Unexpectedly, we found that cytokine CCL5, CXCL9, TNFalpha, and IFNgamma were already significantly upregulated in untreated Foxo4-null mice compared to WT controls despite lack of visible colonic phenotypes. Consistent with the exacerbated inflammatory phenotype in TNBS-treated Foxo4 KO mice, expressions of these inflammatory cytokines are further upregulated after TNBS-treatment. In addition, we observed many more inflammatory cytokines that were upregulated in TNBS-treated Foxo4 KO mice, including chemokines (CCL3, 4, 7, 8, 11, 12, 21b and CXCL1, 12, 14), chemokine receptors (CCR7, CCRl2, 8,CXC3CR1), cytokines (IL-1, IL-6, IL-11, IFI205), and cytokine receptors (TNFrsf). Interestingly, many of the anti-bacterial peptides were also up-regulated in TNBS treated Foxo4 KO mice including defensin related cryptdin (Defcr3,5,6, 9,13) and Defcr related sequence (Defcr-cr1,2,10,12). Up-regulation of basal level of IFNgamma, TNFalpha, CCL5, and CXCL9 expression in Foxo4 KO mice is specific to colonic tissues, as no significant difference of these gene transcript levels between wild type and Foxo4 KO mice was observed in other tissues including thymus . IFNgamma, TNFalpha, and IL-1ï¢which are upregulated in TNBS-treated Foxo4 KO mice, are Th1 type cytokines. This is consistent with the Th1 inflammatory phenotype observed in TNBS-treated Foxo4-KO mice. We also tested whether the expression of Th2 cytokines (IL-4, IL-5, and IL-13) is altered in TNBS-treated WT and Foxo4-null mice in comparison to ethanol-treated mice and observed no significant differences suggesting that the TNBS-induced colitis in Foxo4-null FVB mice is predominantly Th1 in nature. Colonic mucosal tissues from five mice per treatment group (untreated, two days after ethanol or TNBS-treatment) were pooled. Total RNA obtained from colon mucosa isolated tendon fascicles subjected to 1 or 24 hours in vitro cyclic tensile strain compared to unstrained control fascicles.
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Project description:This study is to analyze genome-wide occupancy of FoxO4 in WT TH1 cells.
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