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High altitude de-acclimatization leads to long-term immune-suppression via upregulating Nrf2 expression in Tregs [RNA-seq]

ABSTRACT: Introduction: High-altitude exposure imposes hypoxic, low-pressure, and cold conditions that challenge immune homeostasis. The long-term effects of high-altitude de-acclimatization (HADA) remain poorly understood. Objectives: The purpose of this study is to investigate how HADA affects the immune populations, both quantitatively and functionally, and to dissect the underlying molecular mechanisms involved. Methods: Peripheral blood was collected from both human cohorts and mice models while other immune organs including spleen, thymus and bone marrow were obtained from mice models. Proportions of immune cell populations in peripheral blood and other immune organs were analyzed using flow cytometry. The immune-suppressive functions of Tregs were determined by in vitro co-culture with CD8+ T cells. Transcriptomic and chromatin-accessibility feature induced by HADA were obtained through RNA-seq and ATAC-seq. The functional validation of HADA target gene was performed using specific agonist during in vitro co-culture. Results: HADA perturbed the proportions of immune populations in multiple immune site. Both data from human and mice showed increased regulatory T cells (Tregs) and enhanced immune-suppressive function in the peripheral blood. As a consequence, these Tregs mediated long-term immune suppression, impairing the immunity against tumor cells. Multi-omic analyses predicted Nrf2 as the key mediator of molecular alterations in Tregs caused by HADA, which was further confirmed by the functional assay. Conclusion: High-altitude de-acclimatization mediates the expansion of peripheral Tregs and enhances long-lasting immunosuppressive function of Tregs, increasing the probability of serious health consequences. Nrf2 plays as a key regulator mediating the effects of HADA on Tregs. These findings provide novel insights into altitude-related immune regulation and implications for health management in populations transitioning between high and low altitudes.

ORGANISM(S): Mus musculus

PROVIDER: GSE315734 | GEO | 2026/03/18

REPOSITORIES: GEO

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Project description:Introduction: High-altitude exposure imposes hypoxic, low-pressure, and cold conditions that challenge immune homeostasis. The long-term effects of high-altitude de-acclimatization (HADA) remain poorly understood. Objectives: The purpose of this study is to investigate how HADA affects the immune populations, both quantitatively and functionally, and to dissect the underlying molecular mechanisms involved. Methods: Peripheral blood was collected from both human cohorts and mice models while other immune organs including spleen, thymus and bone marrow were obtained from mice models. Proportions of immune cell populations in peripheral blood and other immune organs were analyzed using flow cytometry. The immune-suppressive functions of Tregs were determined by in vitro co-culture with CD8+ T cells. Transcriptomic and chromatin-accessibility feature induced by HADA were obtained through RNA-seq and ATAC-seq. The functional validation of HADA target gene was performed using specific agonist during in vitro co-culture. Results: HADA perturbed the proportions of immune populations in multiple immune site. Both data from human and mice showed increased regulatory T cells (Tregs) and enhanced immune-suppressive function in the peripheral blood. As a consequence, these Tregs mediated long-term immune suppression, impairing the immunity against tumor cells. Multi-omic analyses predicted Nrf2 as the key mediator of molecular alterations in Tregs caused by HADA, which was further confirmed by the functional assay. Conclusion: High-altitude de-acclimatization mediates the expansion of peripheral Tregs and enhances long-lasting immunosuppressive function of Tregs, increasing the probability of serious health consequences. Nrf2 plays as a key regulator mediating the effects of HADA on Tregs. These findings provide novel insights into altitude-related immune regulation and implications for health management in populations transitioning between high and low altitudes.

Project description:In humans and other species, Longlong-term hypoxia (LTH) during pregnancy can lead to intrauterine growth restriction with reduced body/brain weight, dysregulation of cerebral blood flow (CBF), and other problems in humans and rodents. In contrast, sheep appear to undergo relatively successful acclimatization, not demonstrating any of the above-mentioned problems except at extremely high altitude. To identify the signal transduction genetic pathways and those critical molecules, which may be involved in acclimatization to high altitude LTH, we conducted microarray with advanced bioinformatic analysis on carotid arteries (CA) from the normoxic near-term ovine fetus at sea-level and those acclimatized to high altitude for 110+ days during gestation. In response to LTH acclimatization, in fetal CA we identified, mRNA from 38 genes upregulated (> 2 fFold; (P < 0.05) and 9 genes downregulated (> 2-f Fold; (P < 0.05). The major genes with upregulated mRNA were SLC1A3, Insulin-like growth factor (IGF) binding protein 3, IGF type 2 receptor, transforming growth factor (TGF) Beta-3, and genes involved in the AKT and BCL2 signal transduction networks. The majority of genes with upregulated mRNA have a common motif for Pbx/Knotted homeobox in the promoter region, and Sox family binding sites in the 3M-bM-^@M-^Y un -translated region (UTR). Genes with downregulated mRNA included those involved in the P53 pathway and 5-lipoxygenase activating proteins. The promoter region of all genes with downregulated mRNA, had a common 49 bp region, with a binding site for DOT6 and TOD6, components of the RPD3 histone deacetylase complex RPD3C(L). We also identified miRNA complementary to a number of the altered genes. Thus, the present study identified molecules in the ovine fetus, which may help it to play a role in the acclimatizatione successfully response to high-altitude associated LTH. In these series of experiments we examined changes in gene expression in sheep carotids. Pregnant sheep and non-pregnant adult sheep were exposed to 110 days of hypoxia at 3801 meters of altitude. Carotid arteries from fetuses from non-pregnant adult from sea-level controls and those from high-altitude were compared by Agilent ovine custom array

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High altitude de-acclimatization leads to long-term immune-suppression via upregulating Nrf2 expression in Tregs [RNA-seq]

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