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

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 CD8⁺ T 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 CD8⁺ T 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 CD8⁺ T 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.