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Ferritin heavy chain supports stability and function of the regulatory T cell lineage

ABSTRACT: Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten-eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential co-factor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation.

SUBMITTER: Dr. Qian Wu

PROVIDER: S-SCDT-10_1038-S44318-024-00064-X | biostudies-other |

REPOSITORIES: biostudies-other

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Ferritin heavy chain supports stability and function of the regulatory T cell lineage.

Project description:Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten-eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation.

| S-EPMC11021483 | biostudies-literature

Oligodendrocytes Provide Antioxidant Defense Function for Neurons by Secreting Ferritin Heavy Chain.

Project description:An evolutionarily conserved function of glia is to provide metabolic and structural support for neurons. To identify molecules generated by glia and with vital functions for neurons, we used Drosophila melanogaster as a screening tool, and subsequently translated the findings to mice. We found that a cargo receptor operating in the secretory pathway of glia was essential to maintain axonal integrity by regulating iron buffering. Ferritin heavy chain was identified as the critical secretory cargo, required for the protection against iron-mediated ferroptotic axonal damage. In mice, ferritin heavy chain is highly expressed by oligodendrocytes and secreted by employing an unconventional secretion pathway involving extracellular vesicles. Disrupting the release of extracellular vesicles or the expression of ferritin heavy chain in oligodendrocytes causes neuronal loss and oxidative damage in mice. Our data point to a role of oligodendrocytes in providing an antioxidant defense system to support neurons against iron-mediated cytotoxicity.

| S-EPMC7116799 | biostudies-literature

The role of ferritin heavy chain (Fth) in polymicrobial sepsis.

Project description:We systematically assessed the transcriptomic changes of livers of MxCreFthD/D vs. Fthlox/lox mice after induction of polymicrobial sepsis using Cecal Ligation and Puncture. Data indicates a distinct set of genes differentially regulated between MxCreFthD/D and Fthlox/lox mice after sepsis induction reflecting altered iron and glucose metabolism.

2017-08-15 | GSE92703 | GEO

Counteraction of myocardial ferritin heavy chain deficiency by heme oxygenase-1

Project description:To investigate the functional significance of myocardial ferritin heavy chain (FtH) in a model of acute myocardial infarction (MI). FtH was deleted using FtH floxed mice and Sm-22 Cre mice on a C57/bl6 background At 3 hours following 45 minutes of ischemia induced via ligation of left ant. decsending coronary artery, ischemic regions were identified, dissected, and total RNA was isolated fand gene expression profiling analysis using data obtained from RNA-seq of 3 different animals. RNA Total RNA isolated from left ventricle under homeostatic (bseline conditions) served as negative ctr. (n=3/group)

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Ferritin Heavy Chain Binds Peroxiredoxin 6 and Inhibits Cell Proliferation and Migration.

Project description:The H Ferritin subunit (FTH1), as well as regulating the homeostasis of intracellular iron, is involved in complex pathways that might promote or inhibit carcinogenesis. This function may be mediated by its ability to interact with different molecules. To gain insight into the FTH1 interacting molecules, we analyzed its interactome in HEK293T cells. Fifty-one proteins have been identified, and among them, we focused our attention on a member of the peroxiredoxin family (PRDX6), an antioxidant enzyme that plays an important role in cell proliferation and in malignancy development. The FTH1/PRDX6 interaction was further supported by co-immunoprecipitation, in HEK293T and H460 cell lines and by means of computational methods. Next, we demonstrated that FTH1 could inhibit PRDX6-mediated proliferation and migration. Then, the results so far obtained suggested that the interaction between FTH1/PRDX6 in cancer cells might alter cell proliferation and migration, leading to a less invasive phenotype.

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Caffeine Positively Modulates Ferritin Heavy Chain Expression in H460 Cells: Effects on Cell Proliferation.

Project description:Both the methylxanthine caffeine and the heavy subunit of ferritin molecule (FHC) are able to control the proliferation rate of several cancer cell lines. While caffeine acts exclusively as a negative modulator of cell proliferation, FHC might reduce or enhance cell viability depending upon the different cell type. In this work we have demonstrated that physiological concentrations of caffeine reduce the proliferation rate of H460 cells: along with the modulation of p53, pAKT and Cyclin D1, caffeine also determines a significant FHC up-regulation through the activation of its transcriptional efficiency. FHC plays a central role in the molecular pathways modulated by caffeine, ending in a reduced cell growth, since its specific silencing by siRNA almost completely abolishes caffeine effects on H460 cell proliferation. These results allow the inclusion of ferritin heavy subunits among the multiple molecular targets of caffeine and open the way for studying the relationship between caffeine and intracellular iron metabolism.

| S-EPMC5033359 | biostudies-literature

Lipid droplets and ferritin heavy chain: a devilish liaison in human cancer cell radioresistance.

Project description:Although much progress has been made in cancer treatment, the molecular mechanisms underlying cancer radioresistance (RR) as well as the biological signatures of radioresistant cancer cells still need to be clarified. In this regard, we discovered that breast, bladder, lung, neuroglioma, and prostate 6 Gy X-ray resistant cancer cells were characterized by an increase of lipid droplet (LD) number and that the cells containing highest LDs showed the highest clonogenic potential after irradiation. Moreover, we observed that LD content was tightly connected with the iron metabolism and in particular with the presence of the ferritin heavy chain (FTH1). In fact, breast and lung cancer cells silenced for the FTH1 gene showed a reduction in the LD numbers and, by consequence, became radiosensitive. FTH1 overexpression as well as iron-chelating treatment by Deferoxamine were able to restore the LD amount and RR. Overall, these results provide evidence of a novel mechanism behind RR in which LDs and FTH1 are tightly connected to each other, a synergistic effect that might be worth deeply investigating in order to make cancer cells more radiosensitive and improve the efficacy of radiation treatments.

| S-EPMC8497056 | biostudies-literature

Value of Ferritin Heavy Chain (FTH1) Expression in Diagnosis and Prognosis of Renal Cell Carcinoma.

Project description:BACKGROUND Serum ferritin is a useful tumor marker for renal cell carcinoma (RCC). However, the expression of ferritin heavy chain (FTH1), the main subunit of ferritin, is unclear in primary RCC tissues. In this study, we investigated FTH1 mRNA expression and its diagnostic and prognostic value in RCC. MATERIAL AND METHODS The mRNA expression of FTH1 was analyzed using including Oncomine, Gene Expression Omnibus, and Cancer Genome Atlas datasets, while the protein level of FTH1 was analyzed using the Human Protein Atlas database. The associations between FTH1 and clinicopathologic characteristics and survival time and Cox multivariate survival analysis were analyzed using SPSS 22.0 software. A meta-analysis was performed to assess consistency of FTH1 expression. GO, KEGG, and PPI analyses were used to predict biological functions. RESULTS According to TCGA data, overexpression of FTH1 was detected in 890 RCC tissues (15.2904±0.63157) compared to 129 normal kidney tissues (14.4502±0.51523, p<0.001). Among the clinicopathological characteristics evaluated, patients with increased pathologic T staging, lymph node metastasis, and distant metastasis were significantly associated with higher expression of FTH1. Elevated FTH1 mRNA levels were correlated with worse prognosis of RCC patients. Cox multivariate survival analysis indicated that age, stage, and M stage were predictors of poor prognosis in patients with RCC. CONCLUSIONS Our data suggest that FTH1 expression is an effective prognostic and diagnosis biomarker for RCC.

| S-EPMC6537665 | biostudies-literature

Stability of the regulatory T cell lineage in vivo.

Project description:Tissue maintenance and homeostasis can be achieved through the replacement of dying cells by differentiating precursors or self-renewal of terminally differentiated cells or relies heavily on cellular longevity in poorly regenerating tissues. Regulatory T cells (T(reg) cells) represent an actively dividing cell population with critical function in suppression of lethal immune-mediated inflammation. The plasticity of T(reg) cells has been actively debated because it could factor importantly in protective immunity or autoimmunity. By using inducible labeling and tracking of T(reg) cell fate in vivo, or transfers of highly purified T(reg) cells, we have demonstrated notable stability of this cell population under physiologic and inflammatory conditions. Our results suggest that self-renewal of mature T(reg) cells serves as a major mechanism of maintenance of the T(reg) cell lineage in adult mice.

| S-EPMC4262151 | biostudies-literature

Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction.

Project description:Interaction of the chemokine CXCL12 with its receptor CXCR4 promotes neuronal function and survival during embryonic development and throughout adulthood. Previous studies indicated that ?-opioid agonists specifically elevate neuronal levels of the protein ferritin heavy chain (FHC), which negatively regulates CXCR4 signaling and affects the neuroprotective function of the CXCL12/CXCR4 axis. Here, we determined that CXCL12/CXCR4 activity increased dendritic spine density, and also examined FHC expression and CXCR4 status in opiate abusers and patients with HIV-associated neurocognitive disorders (HAND), which is typically exacerbated by illicit drug use. Drug abusers and HIV patients with HAND had increased levels of FHC, which correlated with reduced CXCR4 activation, within cortical neurons. We confirmed these findings in a nonhuman primate model of SIV infection with morphine administration. Transfection of a CXCR4-expressing human cell line with an iron-deficient FHC mutant confirmed that increased FHC expression deregulated CXCR4 signaling and that this function of FHC was independent of iron binding. Furthermore, examination of morphine-treated rodents and isolated neurons expressing FHC shRNA revealed that FHC contributed to morphine-induced dendritic spine loss. Together, these data implicate FHC-dependent deregulation of CXCL12/CXCR4 as a contributing factor to cognitive dysfunction in neuroAIDS.

| S-EPMC3904611 | biostudies-literature

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