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HIF-1α/HMOX1-Mediated Ferroptosis in Macrophages Exacerbates Malaria Progression
Guikuan Liang1,2, Jiajie Li2, Xiongyu Xie1,2
1Department of Infectious Diseases, Key Laboratory for Major Obsteric Diseases of Guangdong Province, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Abstract:
The spleen orchestrates anti-malarial immunity, with its macrophages phagocytizing Plasmodium-infected blood cells (iRBCs). While regulated cell death (RCD) has been extensively studied in various diseases, the relationship between regulatory cell death of splenic macrophages and the progression of malaria infection remains unexplored. In this study, we identify that Plasmodium infection triggers ferroptosis in splenic macrophages characterized by aberrant HMOX1 upregulation concomitant with HIF-1α downregulation. Mechanistically, the loss of HIF-1α signaling fails to restrain HMOX1 expression, leading to Fe2+ overload. Fer-1 inhibits ferroptosis in iRBC-exposed macrophages in vitro. P. yoelii-infected mice show elevated ferroptosis biomarkers in splenic macrophages, reversible by Fer-1 treatment. Additionally, compared to GPX4flox/flox infected mice, the conditional knockout infected mice (GPX4flox/flox Lyz2Cre+) display worsened health conditions and more severe parasitemia. Moreover, identical ferroptosis signature is detected in monocytes from malaria patient PBMCs, confirming cross-species conservation. In conclusion, these findings suggest that Plasmodium yoelii NSM infection triggers ferroptosis in splenic macrophages, which exacerbates malaria progression. Targeting the HIF-1α/HMOX1 axis to modulate macrophage ferroptosis alleviates the progression of Plasmodium infection, providing crucial mechanistic insights that warrant cautious exploration for host-directed interventions.
Insights
Malaria infection causes splenic macrophages to undergo ferroptosis, a form of cell death that worsens the disease. Inhibiting this process may offer new malaria treatments.
Area of Science:
- Immunology
- Cell Biology
- Parasitology
Background:
- The spleen plays a key role in anti-malarial immunity, involving macrophage phagocytosis of Plasmodium-infected red blood cells (iRBCs).
- The role of regulated cell death (RCD) in splenic macrophages during malaria progression is not well understood.
Purpose of the Study:
- To investigate the link between splenic macrophage RCD and malaria progression.
- To identify the specific type of RCD triggered by Plasmodium infection and its underlying mechanisms.
Main Methods:
- Analyzing ferroptosis biomarkers in splenic macrophages of Plasmodium yoelii-infected mice.
- Investigating the role of HIF-1α and HMOX1 in ferroptosis.
- Utilizing Fer-1 to inhibit ferroptosis in vitro and in vivo.
- Comparing disease progression in wild-type and GPX4 conditional knockout mice.
Main Results:
- Plasmodium infection induces ferroptosis in splenic macrophages, marked by increased HMOX1 and decreased HIF-1α.
- Loss of HIF-1α signaling leads to uncontrolled HMOX1 expression and iron overload.
- Fer-1 treatment reduced ferroptosis in vitro and improved outcomes in infected mice.
- GPX4 knockout mice exhibited exacerbated malaria symptoms and higher parasitemia.
- Ferroptosis signatures were conserved in monocytes from malaria patients.
Conclusions:
- Plasmodium yoelii infection triggers splenic macrophage ferroptosis, contributing to malaria progression.
- Modulating the HIF-1α/HMOX1 pathway to control macrophage ferroptosis can alleviate malaria.
- These findings offer insights for developing host-directed malaria interventions.
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