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<p> <?tk 1?>Cerebral malaria (CM), a life-threatening neurological complication of <i>Plasmodium falciparum</i> infection, is characterized by severe neuroinflammation and long-term neurological sequelae. Central nervous system inflammation, driven by brain-infiltrated CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> T cells. This pyroptotic pathway amplifies neuroinflammation and exacerbates neuronal injury. Genetic ablation of <i>Gsdme</i> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年8月14日

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  • Jun Wang,
  • Qinghao Zhu,
  • Guodong Tong,
  • Kangjie Yu,
  • Jiao Liang,
  • Yuxiao Huang,
  • Yi Wang,
  • Chao Yang,
  • Tong Li,
  • Weilu Liang,
  • Ganze Li,
  • Xiaoran Liu,
  • Jiayi Sun,
  • Yinghui Li,
  • Yan Shen,
  • Ya Zhao

摘要

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.