Iron capture through CD71 dictates perinatal and tumoral Treg expansion modulating iron homeostasis and gut microbiota colonization
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ABSTRACT:
PROVIDER: PRJNA876746 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21420429_1.fastq.gz | Fastqsanger.gz | |||
| SRR21420429_2.fastq.gz | Fastqsanger.gz | |||
| SRR21420430_1.fastq.gz | Fastqsanger.gz | |||
| SRR21420430_2.fastq.gz | Fastqsanger.gz | |||
| SRR21420431_1.fastq.gz | Fastqsanger.gz |
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Project description:Beside suppressing immune responses, regulatory T cells (Tregs) maintain tissue homeostasis and control systemic metabolism. Whether iron, a fundamental element for all living cells, is required for Treg expansion, is completely unknown. Here, we showed that the transferrin receptor CD71 was upregulated on activated proliferating Tregs infiltrating human liver cancer. Mice with a Treg-restricted CD71 deficiency spontaneously developed a scurfy-like disease, caused by a severe impairment in perinatal Treg expansion. CD71-null Tregs display decreased proliferation and mitochondrial functions, and a tissue-Treg signature loss. In the perinatal life, CD71 deficiency in Tregs triggered a hepatic response to iron overload, characterized by increased hepcidin transcription and iron accumulation in macrophages. A lower bacterial diversity, and a reduction of beneficial species, were detected in the faecal microbiota of CD71 conditional knock-out neonates. Our findings indicate that the CD71-mediated iron absorption is required for Treg perinatal expansion and controls the systemic iron homeostasis, which in turn shapes the bacterial gut colonization.
2024-07-02 | GSE212688 | GEO
Project description:Background: Perinatal iron deficiency (ID) targets the hippocampus and leads to long-term cognitive deficits. These deficits remain even after iron repletion, suggesting that further insight into the mechanisms of cognitive deficits and adjunct treatments are needed. Intranasal insulin improves cognitive deficits in adult humans with Alzheimer’s disease and type 2 diabetes and could provide benefits in ID-induced neurological dysfunction. Objective: Assess the effects of intranasal insulin administration on the hippocampal transcriptome in rat model of perinatal ID. Methods: Perinatal ID was induced using a low iron diet from gestational day 3 until postnatal day (P) 7, followed by an iron sufficient (IS) diet through P21. Intranasal insulin was administered at a dose of 0.3 IU, twice daily from P8 to P21. Hippocampi were removed on P21 from IS control, ID control, IS insulin, and ID insulin groups. Total RNA was isolated and profiled using TruSeq next-generation sequencing (Illumina). Gene expression profiles were characterized using custom Galaxy workflows and expression patterns were examined using Ingenuity Pathways Analysis (Qiagen) (n = 7-9 per group). Results: Transcriptomic profiling revealed that mitochondrial biogenesis and flux, oxidative phosphorylation, quantity of neurons, CREB signaling in neurons, and RICTOR-based mTOR signaling were disrupted with ID and positively affected by insulin treatment with the most benefit observed in the ID insulin group. Conclusions: Both perinatal ID and insulin administration altered gene expression in the developing hippocampus. Intranasal insulin treatment reversed the adverse effects of ID on many molecular pathways and should be further explored as an adjunct therapy in perinatal ID.
2023-04-20 | GSE220770 | GEO
Project description:Iron metabolism is pivotal for cell fitness in the mammalian host. However, its role in group 3 innate lymphoid cells (ILC3s) is unknown. Here we show that transferrin receptor CD71-mediated iron metabolism cell-intrinsically controls ILC3 maintenance, cytokine production and host protection against Citrobacter rodentium infection, and metabolically affects mitochondrial respiration by switching of oxidative phosphorylation toward glycolysis. Iron deprivation or Tfrc deficiency reduces the expression and/or activity of the aryl hydrocarbon receptor (Ahr), a ligand-dependent transcription factor and a key ILC3 regulator. Furthermore, consistent with its role in generation of Ahr ligand, microbiome exerts a negative impact on CD71 expression in an Ahr-dependent manner. Genetic ablation or activation of Ahr in ILC3s leads to CD71 upregulation or downregulation, respectively, suggesting an active suppression of CD71 by Ahr. Iron overload partially restores defective ILC3 compartment in the small intestine of Ahr-deficient mice, representing compensatory action of CD71 upregulation during Ahr deficiency. Mechanistically, Ahr directly binds to the promoter region of the Tfrc locus to inhibit Tfrc transcription. These data collectively demonstrate an under-appreciated role of the Ahr-CD71-iron axis in regulation of ILC3 maintenance and function.
2023-07-10 | GSE222619 | GEO
Project description:We describe the unique enrichment of erythroid-megakaryocyte primed CD71+ phenotypic HSC/MPPs in steady-state PB.
2021-12-17 | GSE191084 | GEO
Project description:Role of the Ahr-CD71-iron axis in regulation of ILC3 maintenance and function
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Project description:Iron deficiency (ID) is common during gestation and in early infancy and can alter developmental trajectories with lasting consequences on cardiovascular health. While the effects of ID and anemia on the mature heart are well documented, comparatively little is known about their effects and mechanisms on offspring cardiac development and function in the neonatal period. Female Sprague-Dawley rats were fed an iron-restricted or iron-replete diet before and during pregnancy. Cardiac function was assessed in a cohort of offspring on postnatal days (PD) 4, 14, and 28 by echocardiography; a separate cohort was euthanized for tissue collection and hearts underwent quantitative shotgun proteomic analysis. ID reduced body weight and increased relative heart weights at all time points assessed, despite recovering from anemia by PD28. Echocardiographic studies revealed unique functional impairments in ID male and female offspring, characterized by greater systolic dysfunction in the former and greater diastolic dysfunction in the latter. Proteomic analysis revealed down-regulation of structural components by ID, as well as enriched cellular responses to stress; in general, these effects were more pronounced in males. ID causes functional changes in the neonatal heart, which may reflect an inadequate or maladaptive compensation to anemia. This identifies systolic and diastolic dysfunction as comorbidities to perinatal ID anemia which may have important implications for both the short- and long-term cardiac health of newborn babies. Furthermore, therapies which improve cardiac output may mitigate the effects of ID on organ development.
2024-10-03 | PXD043588 | Pride
Project description:Iron metabolism is pivotal for cell fitness in the mammalian host. However, its role in group 3 innate lymphoid cells (ILC3s) is unknown. Here we show that transferrin receptor CD71-mediated iron metabolism cell-intrinsically controls ILC3 maintenance, cytokine production and host protection against Citrobacter rodentium infection, and metabolically affects mitochondrial respiration by switching of oxidative phosphorylation toward glycolysis. Iron deprivation or Tfrc deficiency reduces the expression and/or activity of the aryl hydrocarbon receptor (Ahr), a ligand-dependent transcription factor and a key ILC3 regulator. Furthermore, consistent with its role in generation of Ahr ligand, microbiome exerts a negative impact on CD71 expression in an Ahr-dependent manner. Genetic ablation or activation of Ahr in ILC3s leads to CD71 upregulation or downregulation, respectively, suggesting an active suppression of CD71 by Ahr. Iron overload partially restores defective ILC3 compartment in the small intestine of Ahr-deficient mice, representing compensatory action of CD71 upregulation during Ahr deficiency. Mechanistically, Ahr directly binds to the promoter region of the Tfrc locus to inhibit Tfrc transcription. These data collectively demonstrate an under-appreciated role of the Ahr-CD71-iron axis in regulation of ILC3 maintenance and function.
2023-07-10 | GSE222620 | GEO
Project description:Iron metabolism is pivotal for cell fitness in the mammalian host. However, its role in group 3 innate lymphoid cells (ILC3s) is unknown. Here we show that transferrin receptor CD71-mediated iron metabolism cell-intrinsically controls ILC3 maintenance, cytokine production and host protection against Citrobacter rodentium infection, and metabolically affects mitochondrial respiration by switching of oxidative phosphorylation toward glycolysis. Iron deprivation or Tfrc deficiency reduces the expression and/or activity of the aryl hydrocarbon receptor (Ahr), a ligand-dependent transcription factor and a key ILC3 regulator. Furthermore, consistent with its role in generation of Ahr ligand, microbiome exerts a negative impact on CD71 expression in an Ahr-dependent manner. Genetic ablation or activation of Ahr in ILC3s leads to CD71 upregulation or downregulation, respectively, suggesting an active suppression of CD71 by Ahr. Iron overload partially restores defective ILC3 compartment in the small intestine of Ahr-deficient mice, representing compensatory action of CD71 upregulation during Ahr deficiency. Mechanistically, Ahr directly binds to the promoter region of the Tfrc locus to inhibit Tfrc transcription. These data collectively demonstrate an under-appreciated role of the Ahr-CD71-iron axis in regulation of ILC3 maintenance and function.
2023-07-10 | GSE222008 | GEO