2. Academic Validation
  3. GSDME-dependent astrocyte pyroptosis promotes the progression of neuroinflammation in experimental cerebral malaria

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

  • Apoptosis. 2025 Aug 14. doi: 10.1007/s10495-025-02140-x.
Jun Wang # 1,  Qinghao Zhu # 1,  Guodong Tong # 2,  Kangjie Yu 3,  Jiao Liang 1,  Yuxiao Huang 1,  Yi Wang 1,  Chao Yang 2,  Tong Li 4,  Weilu Liang 5,  Ganze Li 1,  Xiaoran Liu 5,  Jiayi Sun 2,  Yinghui Li 6,  Yan Shen 7,  Ya Zhao 8
Affiliations

Affiliations

  • 1 Department of Medical Microbiology and Parasitology, Air Force Medical University, Xi'an, China.
  • 2 College of Life Sciences, Northwest University, Xi'an, China.
  • 3 Department of Pathology, Air Force Hospital of Eastern Theater, Nanjing, China.
  • 4 College of Basic Medical Sciences, Yan'an University, Yan'an, China.
  • 5 School of Basic Medical Sciences, Air Force Medical University, Xi'an, China.
  • 6 Department of Medical Microbiology and Parasitology, Air Force Medical University, Xi'an, China. 375576040@qq.com.
  • 7 Department of Medical Microbiology and Parasitology, Air Force Medical University, Xi'an, China. 37762810@qq.com.
  • 8 Department of Medical Microbiology and Parasitology, Air Force Medical University, Xi'an, China. zhaoya@fmmu.edu.cn.
  • # Contributed equally.
PMID: 40813537 DOI: 10.1007/s10495-025-02140-x
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 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.

Keywords

Astrocyte; Cerebral malaria; GSDME; Neuroinflammation; Pyroptosis.

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