Ferroptosis participates in neuron damage in experimental cerebral malaria and is partially induced by activated CD8+ T cells

Cerebral malaria is the most serious complication of malaria infection, with 26% of surviving children having neurological sequelae, which may be caused by neuron damage, but the mechanism is not clear. Ferroptosis has been reported to play an important role in neuron damage in several nervous system diseases. However, the occurrence of ferroptosis in experimental cerebral malaria (ECM) pathogenesis is still unknown. In this study, we firstly detected increased levels of malondialdehyde (MDA) and iron, which are indicators of ferroptosis, in the cerebrum of ECM mice. Some important regulators of ferroptosis, including upregulated expression of transferrin receptor 1 (TfR1) and acyl-CoA synthetase long-chain family member 4 (ACSL4), and downregulation of glutathione peroxidase 4 (GPX4) levels, were also confirmed in ECM mice. Consistently, neuron damage, which was detected in the cerebrum of ECM mice, was positively correlated with reduced GPX4 expression and furtherly rescued by administration of the ferroptosis inhibitor ferrostatin-1 (Fer-1). In addition, primary neurons were damaged by activated CD8(+) T cells, an effect that was also partially rescued by Fer-1 on amyloid precursor protein expression and mitochondrial membrane potential levels in vitro. Activated CD8(+) T cells were also shown to infiltrate the cerebrum of ECM mice and upregulate TfR1 expression in primary neurons, which may be an important event for inducing ferroptosis in ECM. Altogether, we show that ferroptosis contributes to neuron damage in ECM pathogenesis, and activated CD8(+) T cells may be important inducers of neuronal ferroptosis. Hence, targeting ferroptosis may be a promising adjuvant therapeutic strategy for neurological sequelae in patients with cerebral malaria.

Automated summary

Cerebral malaria is a severe complication of malaria infection, with the potential for long-term neurological damage. This study investigates the role of ferroptosis, a cell death pathway, in the development of cerebral malaria. The researchers found evidence of increased markers of ferroptosis in the brains of mice with experimental cerebral malaria, as well as alterations in key regulators of ferroptosis. Additionally, activated CD8(+) T cells were shown to cause neuron damage, a process partially rescued by a ferroptosis inhibitor. These findings suggest that targeting ferroptosis could be a promising strategy for treating the neurological sequelae of cerebral malaria.