GSDME-dependent astrocyte pyroptosis promotes the progression of neuroinflammation in experimental cerebral malaria.

Abstract

Cerebral malaria (CM), a life-threatening neurological complication of Plasmodium falciparum infection, is characterized by severe neuroinflammation and long-term neurological sequelae. Central nervous system inflammation, driven by brain-infiltrated CD8T cells, represents a hallmark pathological feature of CM. In this study, we demonstrate that astrocytes, a critical component of the blood-brain barrier and neurovascular unit, exhibit a robust interferon-γ response during CM, facilitating CD8T cell recruitment into the brain parenchyma and antigen presentation to these immune cells. Importantly, we identify gasdermin E (GSDME)-dependent pyroptosis in astrocytes, a process triggered by brain-infiltrated CD8T cells. This pyroptotic pathway amplifies neuroinflammation and exacerbates neuronal injury. Genetic ablation of Gsdme or pharmacological inhibition of GSDME activation by mannose significantly attenuated brain inflammation and damage in a murine CM model. Our findings establish, for the first time, that GSDME-dependent astrocyte pyroptosis critically exacerbates neuroinflammation in CM. These results highlight GSDME as a novel therapeutic target for mitigating CM and related neuroinflammatory diseases.