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

Abstract

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.

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“…Whether in the process of innate immunity or adaptive immunity, macrophages play a crucial role in the infection of the body [ 3 ]. Ferroptosis is a new form of adaptive and programmed cell death first proposed by Brent r. Stockwell in 2012 [ 4 ]. Ferroptosis is a new type of programmed cell death that is iron dependent and different from apoptosis, cell necrosis, and autophagy.…”

Bioinorganic Modulators of Ferroptosis: A Review of Recent Findings

“…Other than that, the administration of gallium–ellagic acid nanoparticles caused an increase of GSH and superoxide dismutase, the latter being one of the major elements of cellular protection against ROS-mediated oxidative damage [ 77 ]. Less malondialdehyde, on the other hand, was indicative of an inhibited lipid peroxidation process in cancer cells [ 78 ]. The gallium atoms likely contributed to normalizing the serum level of iron, as reflected by lower total iron-binding capacity (TIBC) relative to the DMBA iron-deficient group, where much of iron supply was consumed by malignant cells [ 75 ].…”

Iron overload triggering ECM-mediated Hippo/YAP pathway in follicle development: a hypothetical model endowed with therapeutic implications

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