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Isolation and Analysis of Brain-sequestered Leukocytes from Plasmodium berghei ANKA-infected Mice
Published on: January 2, 2013
Ferrostatin-1 alleviates experimental cerebral malaria by regulating immune cell functions and brain endothelial
Shijie Yao1, Xiaoliang Zhou2, Ting Liao2
1Department of Immunology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China; National Clinical Research Center for Laboratory Medicine, Department of Laboratory Medicine, The First Hospital of China Medical University, Shenyang, Liaoning, China.
Abstract:
Cerebral malaria (CM), a life-threatening complication of Plasmodium falciparum infection, is characterized by dysregulated immune responses and blood-brain barrier (BBB) damage. In this study, we found that iron metabolic disorders occurred in the spleen and brain tissues in response to Plasmodium berghei ANKA (PbA) infection in a murine CM model. PbA infection promoted lipid peroxidation and induced ferroptosis, manifested as the accumulation of iron ion, elevation of reactive oxygen species and lipid peroxide, upregulated expression of the ferroptosis-related protein TFRC and ACSL4, and downregulated expression of SLC7A11 and GPX4. Ferrostatin-1 (Fer-1), is widely used as a reference compound as a synthetic radical-trapping antioxidant, which inhibits ferroptosis by suppressing lipid peroxide formation. Intervention with Fer-1 ameliorated iron metabolic disorders, reduced lipid peroxidation, decreased parasitemia, extended survival time, alleviated neurological symptoms, and improved BBB integrity. Mechanistically, Fer-1 exerted dual-axis regulation: firstly, enhancing the antigen-presenting capacity of dendritic cells (DCs) by upregulating MHC II, CD80/86, promoting M1 polarization of macrophages, modulating CD4+ T cell responses to increase IFN-γ+ Th1 cells and Treg cell proportions for balancing pro-inflammatory and anti-inflammatory reactions; secondly inhibiting ferroptosis in brain microvascular endothelial cells, downregulating chemokines CXCL9/CXCL10 and adhesion molecules ICAM-1/VCAM-1, and reducing cerebral infiltration of CD8+ T cells. Our study confirms that Fer-1 alleviates ECM pathological progression through dual mechanisms "immune activation-endothelial protection", providing a novel ferroptosis-targeted strategy for CM prevention and treatment.
Insights
Ferrostatin-1 (Fer-1) treatment mitigates cerebral malaria (CM) by targeting ferroptosis, a cell death pathway. This antioxidant drug improves immune responses and protects the blood-brain barrier (BBB), offering a new therapeutic strategy for CM.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Cerebral malaria (CM) is a severe Plasmodium falciparum complication involving immune dysregulation and blood-brain barrier (BBB) damage.
- Iron metabolic dysfunction, lipid peroxidation, and ferroptosis are implicated in CM pathogenesis.
- Plasmodium berghei ANKA (PbA) infection in mice serves as a model for studying CM.
Purpose of the Study:
- To investigate the role of iron metabolism and ferroptosis in a murine model of cerebral malaria.
- To evaluate the therapeutic potential of Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, in mitigating CM pathology.
Main Methods:
- Induction of CM in mice using Plasmodium berghei ANKA (PbA) infection.
- Assessment of iron metabolism, lipid peroxidation, and ferroptosis markers (TFRC, ACSL4, SLC7A11, GPX4).
- Treatment with Ferrostatin-1 (Fer-1) and evaluation of its effects on parasitemia, survival, neurological symptoms, BBB integrity, immune cell function, and inflammatory markers.
Main Results:
- PbA infection induced iron dysregulation, increased lipid peroxidation, and ferroptosis in spleen and brain tissues.
- Fer-1 treatment reduced iron accumulation, lipid peroxidation, decreased parasitemia, extended survival, and improved neurological and BBB integrity.
- Fer-1 modulated dendritic cell and macrophage function, promoted Th1 and Treg cell responses, inhibited ferroptosis in brain endothelial cells, and reduced neuroinflammation and CD8+ T cell infiltration.
Conclusions:
- Ferrostatin-1 (Fer-1) alleviates cerebral malaria pathology through a dual mechanism involving immune activation and endothelial protection.
- Targeting ferroptosis with Fer-1 represents a promising therapeutic strategy for preventing and treating cerebral malaria.
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