High-altitude hypoxia exposure impairs splenic macrophage function, leading to disrupted erythrocyte clearance and iron recycling

Core Concepts

Exposure to high-altitude hypoxia induces ferroptosis in splenic macrophages, leading to a reduction in their erythrophagocytic capacity and impaired iron recycling, which contributes to the development of high-altitude polycythemia.

Abstract

The study investigates the impact of high-altitude hypoxia exposure on the spleen and splenic macrophages, and its implications for the pathogenesis of high-altitude polycythemia (HAPC).
Key highlights:

High-altitude hypoxia exposure (HH) significantly stimulates erythropoiesis, leading to erythrocytosis in mice.
HH exposure causes a sequence of changes in the spleen, including initial splenic contraction followed by splenomegaly.
A key observation is the impairment of the spleen's capacity to process red blood cells (RBCs), primarily attributed to a reduction in splenic macrophages located in the red pulp.
Extended HH exposure leads to increased iron mobilization and the onset of ferroptosis within the spleen, as evidenced by altered expression of iron metabolism and ferroptosis-related proteins.
Single-cell sequencing of splenic tissue demonstrates a marked decrease in macrophage populations after 7 days of HH exposure.
The decrease in red pulp macrophages and erythrophagocytosis results in increased RBC retention in the spleen, likely contributing to continuous RBC production and the progression of HAPC.
In vitro analyses confirm the decline in primary splenic macrophages and induction of ferroptosis under hypoxic conditions, effects that are relieved by pre-treatment with the ferroptosis inhibitor ferrostatin-1.
The study highlights the important role of the spleen and splenic macrophages in the pathogenesis of HAPC, providing insights into disease progression and potential therapeutic targets.

Stats

Exposure to high-altitude hypoxia (HH) for 7 and 14 days significantly increased the number of red blood cells (RBCs), hemoglobin (HGB) content, and hematocrit (HCT) values in mice.
The proportion of reticulocytes in the blood increased after 7 and 14 days of HH exposure.
Splenectomy under HH conditions led to a significant increase in erythrocyte deposition and counts, as well as HGB and HCT levels, compared to sham-operated mice exposed to HH.
The expression of chemokines CCL2, CCL7, Csf1, and Csf2 in the spleen decreased significantly after 7 and 14 days of HH exposure.
The number of monocytes (Ly6C+/CD11b+) in the bone marrow and spleen declined after 7 and 14 days of HH exposure.

Quotes

"Exposure to HH triggered ferroptosis in the spleen, particularly in macrophages. This led to a reduction in macrophage numbers, which was subsequently followed by disruptions in erythrophagocytosis and iron recycling within the spleen."
"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."

Key Insights Distilled From

High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen

by Yang,W.-p., ... at www.biorxiv.org 03-25-2023

https://www.biorxiv.org/content/10.1101/2023.03.23.533972v3

Deeper Inquiries

How do the changes in splenic macrophage function and iron metabolism under high-altitude hypoxia exposure contribute to the development of other high-altitude-related diseases, such as high-altitude cerebral edema or high-altitude pulmonary edema?

The changes in splenic macrophage function and iron metabolism under high-altitude hypoxia exposure can have significant implications for the development of other high-altitude-related diseases. High-altitude exposure leads to hypoxia, which triggers a cascade of events in the body, including increased erythropoiesis and alterations in iron metabolism. In the context of high-altitude cerebral edema (HACE) and high-altitude pulmonary edema (HAPE), these changes can exacerbate the pathophysiology of these conditions.

High-Altitude Cerebral Edema (HACE):

In HACE, the brain experiences swelling due to the accumulation of fluid. The changes in splenic macrophage function and iron metabolism can contribute to this condition by affecting the overall oxygen delivery to the brain. With altered erythropoiesis and impaired erythrocyte clearance in the spleen, there may be an imbalance in oxygen supply and demand in the brain, leading to hypoxia and subsequent cerebral edema.

High-Altitude Pulmonary Edema (HAPE):

HAPE is characterized by the accumulation of fluid in the lungs, leading to respiratory distress. The changes in splenic macrophage function and iron metabolism can impact the oxygen-carrying capacity of the blood. With alterations in erythropoiesis and iron recycling, there may be an increase in red blood cell production and changes in iron availability, which can affect the oxygenation of tissues, including the lungs. This can contribute to the development of HAPE under high-altitude conditions.

Overall, the dysregulation of splenic macrophages and iron metabolism under high-altitude hypoxia exposure can disrupt the delicate balance of oxygen delivery and utilization in the body, potentially exacerbating the development of high-altitude-related diseases like HACE and HAPE.

What are the potential therapeutic interventions that could target the ferroptosis pathway in splenic macrophages to alleviate the progression of high-altitude polycythemia?

Targeting the ferroptosis pathway in splenic macrophages presents a promising therapeutic approach to alleviate the progression of high-altitude polycythemia. Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation, and its modulation can have significant implications for various diseases, including high-altitude polycythemia. Here are some potential therapeutic interventions targeting the ferroptosis pathway in splenic macrophages:

Ferroptosis Inhibitors:

Utilizing ferroptosis inhibitors, such as ferrostatin-1, can help mitigate the effects of ferroptosis in splenic macrophages. By blocking the lipid peroxidation process and iron-dependent cell death, these inhibitors can protect splenic macrophages from ferroptotic damage and maintain their function in erythrocyte clearance.

Iron Chelation Therapy:

Iron chelators can be used to sequester excess iron in the spleen, preventing its accumulation and subsequent induction of ferroptosis. By reducing the availability of free iron, iron chelation therapy can help regulate iron metabolism in splenic macrophages and mitigate the progression of high-altitude polycythemia.

Antioxidant Supplementation:

Antioxidants, such as glutathione and vitamin E, can counteract the oxidative stress associated with ferroptosis. By scavenging free radicals and protecting cell membranes from lipid peroxidation, antioxidant supplementation can enhance the resilience of splenic macrophages to ferroptotic stimuli.

Regulation of Iron Metabolism:

Modulating the expression of iron metabolism-related proteins, such as Ft-L, Ft-H, and Fpn, can help restore iron homeostasis in splenic macrophages. By promoting proper iron recycling and storage, the progression of high-altitude polycythemia can be mitigated.

Incorporating these therapeutic interventions that target the ferroptosis pathway in splenic macrophages can offer novel strategies to alleviate the progression of high-altitude polycythemia and maintain erythrocyte homeostasis under high-altitude conditions.

Given the crucial role of the spleen in maintaining red blood cell homeostasis, how might the findings from this study inform our understanding of the spleen's involvement in other hematological disorders characterized by abnormal erythropoiesis or erythrocyte clearance?

The findings from this study shed light on the intricate relationship between splenic macrophages, iron metabolism, and erythrocyte dynamics under high-altitude hypoxia exposure. This understanding can be extrapolated to gain insights into the spleen's involvement in other hematological disorders characterized by abnormal erythropoiesis or erythrocyte clearance. Here's how these findings can inform our understanding:

Hematological Disorders with Erythropoiesis Imbalance:

In conditions like hemolytic anemia or thalassemia, where there is excessive destruction of red blood cells, the role of splenic macrophages in erythrocyte clearance becomes crucial. Understanding how alterations in splenic macrophage function impact erythrocyte processing can provide insights into the pathogenesis of these disorders and potential therapeutic targets.

Iron Metabolism Disorders:

Disorders like hereditary hemochromatosis, characterized by iron overload, can affect the spleen's ability to regulate iron metabolism. The findings on iron mobilization and ferroptosis in splenic macrophages under high-altitude conditions can offer parallels to how the spleen responds to iron dysregulation in these disorders.

Autoimmune Hemolytic Anemia:

Autoimmune disorders affecting erythrocytes, such as autoimmune hemolytic anemia, involve the destruction of red blood cells by the immune system. Understanding the impact of altered erythrophagocytosis on RBC clearance in the spleen can provide insights into the immune-mediated mechanisms underlying these disorders.

By extrapolating the findings from this study to other hematological disorders, we can enhance our understanding of the spleen's role in maintaining red blood cell homeostasis and its involvement in the pathophysiology of various conditions characterized by abnormal erythropoiesis or erythrocyte clearance.