High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen
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ABSTRACT:
PROVIDER: PRJNA1095918 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28549394_1.fastq.gz | Fastqsanger.gz | |||
| SRR28549394_2.fastq.gz | Fastqsanger.gz | |||
| SRR28549395_1.fastq.gz | Fastqsanger.gz | |||
| SRR28549395_2.fastq.gz | Fastqsanger.gz |
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Project description:High-altitude polycythemia (HAPC) is a chronic condition prevalent in individuals residing at high altitudes (HA), characterized by an augmented production of red blood cells (RBCs) due to hypoxic conditions. Despite its prevalence, the pathophysiological basis and molecular mechanisms driving HAPC remain largely unelucidated. In our study, we utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O2 to investigate these mechanisms. Our findings revealed that HH exposure significantly stimulates erythropoiesis, leading to erythrocytosis. This was accompanied by a notable sequence of splenic changes, initially characterized by splenic contraction, which subsequently progressed to splenomegaly over 14 days. A key observation was the impairment on the capacity of spleen to process RBCs, primarily attributed to a reduction in splenic macrophages located in the red pulp. Extended HH treatment over 7 and 14 days precipitated increased iron mobilization and the onset of ferroptosis within the spleen. This was evidenced by altered expression levels of iron metabolism and ferroptosis-related proteins, paralleling gene expression patterns observed in human peripheral blood mononuclear cells. Single-cell sequencing of splenic tissue post-HH exposure demonstrated a marked decrease in macrophage populations after 7 days. Our study further disclosed a significant increase in RBCs retention in the spleen following HH exposure, likely a consequence of diminished red pulp macrophages (RPMs) and erythrophagocytosis. This hypothesis was corroborated through comprehensive analyses involving flow cytometry, histological staining, and immunostaining, which collectively provided a detailed understanding of RBCs dynamics under HH conditions. In vitro analyses substantiated the decline in primary splenic macrophages and induction of ferroptosis under hypoxic treatment, effects that were relieved by pre-treatment with the ferroptosis inhibitor ferrostatin-1. Collectively, our data suggest that HH exposure initiates splenic ferroptosis, leading primarily to a decrease in RPMs. This decrease potentially impacts erythrophagocytosis, contributing to increased RBCs retention and subsequent splenomegaly. Such changes could potentially foster continuous RBCs production and accelerate the progress of HAPC. In conclusion, our study highlights the important role of the spleen and splenic macrophages in the pathogenesis of HAPC, providing crucial insights into the disease progression and potential therapeutic targets.
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Project description:High-altitude polycythemia (HAPC) affects individuals living at high altitudes, characterized by increased red blood cells (RBCs) production in response to hypoxic conditions. The exact mechanisms behind HAPC are not fully understood. We utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O2 to investigate these mechanisms. Our findings indicate that HH significantly boosts erythropoiesis, leading to erythrocytosis and splenic changes, including initial contraction to splenomegaly over 14 days. A notable decrease in red pulp macrophages (RPMs) in the spleen, essential for RBCs processing, was observed, correlating with increased iron release and signs of ferroptosis. Prolonged exposure to hypoxia further exacerbated these effects, mirrored in human peripheral blood mononuclear cells. Single-cell sequencing showed a marked reduction in macrophage populations, affecting the spleen's ability to clear RBCs and contributing to splenomegaly. Our findings suggest splenic ferroptosis contributes to decreased RPMs, affecting erythrophagocytosis and potentially fostering continuous RBCs production in HAPC. These insights could guide the development of targeted therapies for HAPC, emphasizing the importance of splenic macrophages in disease pathology.
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Project description:<p>Energy stress depletes ATP and induces cell death. Here we identify an unexpected inhibitory role of energy stress on ferroptosis, a form of regulated cell death induced by iron-dependent lipid peroxidation. We found that ferroptotic cell death and lipid peroxidation can be inhibited by treatments that induce or mimic energy stress. Inactivation of AMP-activated protein kinase (AMPK), a sensor of cellular energy status, largely abolishes the protective effects of energy stress on ferroptosis in vitro and on ferroptosis-associated renal ischaemia-reperfusion injury in vivo. Cancer cells with high basal AMPK activation are resistant to ferroptosis and AMPK inactivation sensitizes these cells to ferroptosis. Functional and lipidomic analyses further link AMPK regulation of ferroptosis to AMPK-mediated phosphorylation of acetyl-CoA carboxylase and polyunsaturated fatty acid biosynthesis. Our study demonstrates that energy stress inhibits ferroptosis partly through AMPK and reveals an unexpected coupling between ferroptosis and AMPK-mediated energy-stress signalling.</p>
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