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Introduction <p>Cardiac arrest (CA) is a life-threatening emergency with a global one-year survival rate of 2%-10%. Brain injury significantly impacts CA outcomes, and neuroinflammation is a key mediator of cerebral damage. Interleukin-17 (IL-17) has been implicated in multiple inflammatory disorders, yet its contribution to CA-induced cerebral damage remains undefined.</p> Objective <p>To elucidate the role of the IL-17 axis in CA-triggered neuroinflammation and to determine whether IL-17 blockade can attenuate hippocampal injury and improve neurologic recovery.</p> Methods <p>Asphyxial CA was induced in adult Sprague-Dawley rats followed by cardiopulmonary resuscitation. Blood–brain barrier (BBB) integrity, Th17 infiltration, astrocyte polarization, and downstream signaling were assessed by flow cytometry, RNA-seq, qRT-PCR, ELISA, immunofluorescence, and western blotting. IL-17&#xa0;A or IL-17RA was neutralized in vivo with specific antibodies, and human SVGP12 astrocytes were employed for mechanistic validation.</p> Results <p>CA promotes Th17 cell differentiation and enhances blood-brain barrier (BBB) permeability, facilitating the infiltration of Th17 cells and their secreted IL-17&#xa0;A/F into the hippocampus. IL-17&#xa0;A/F specifically binds to IL-17RA/RC on astrocytes, activating NF-κB, and MAPK pathways, which drive A1 polarization of astrocytes and exacerbate neuroinflammation. IL-17&#xa0;A neutralization reverses A1 polarization of astrocytes, reduces neuronal apoptosis, improves 24-hour neurologic deficit scores, and enhances survival in CA rats. In vitro, IL-17&#xa0;A induced A1 polarization and inflammatory cytokine release in astrocytes, effects abolished by IL-17RA blockade.</p> Conclusion <p>Our study elucidates the mechanisms underlying CA-induced neuroinflammation and identifies the IL-17&#xa0;A pathway as a potential therapeutic target for mitigating neurological injury following cardiac arrest.</p>

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Cardiac arrest triggers IL-17-mediated neuroinflammation and astrocyte polarization: insights into pathogenesis and intervention

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月14日

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  • Shumei Li,
  • Lei Wang,
  • Qiqi Luo,
  • Maiying Fan,
  • Yixiao Xu,
  • Xiehong Liu,
  • Yiyuan Zhang,
  • Lianhong Zou

摘要

Introduction

Cardiac arrest (CA) is a life-threatening emergency with a global one-year survival rate of 2%-10%. Brain injury significantly impacts CA outcomes, and neuroinflammation is a key mediator of cerebral damage. Interleukin-17 (IL-17) has been implicated in multiple inflammatory disorders, yet its contribution to CA-induced cerebral damage remains undefined.

Objective

To elucidate the role of the IL-17 axis in CA-triggered neuroinflammation and to determine whether IL-17 blockade can attenuate hippocampal injury and improve neurologic recovery.

Methods

Asphyxial CA was induced in adult Sprague-Dawley rats followed by cardiopulmonary resuscitation. Blood–brain barrier (BBB) integrity, Th17 infiltration, astrocyte polarization, and downstream signaling were assessed by flow cytometry, RNA-seq, qRT-PCR, ELISA, immunofluorescence, and western blotting. IL-17 A or IL-17RA was neutralized in vivo with specific antibodies, and human SVGP12 astrocytes were employed for mechanistic validation.

Results

CA promotes Th17 cell differentiation and enhances blood-brain barrier (BBB) permeability, facilitating the infiltration of Th17 cells and their secreted IL-17 A/F into the hippocampus. IL-17 A/F specifically binds to IL-17RA/RC on astrocytes, activating NF-κB, and MAPK pathways, which drive A1 polarization of astrocytes and exacerbate neuroinflammation. IL-17 A neutralization reverses A1 polarization of astrocytes, reduces neuronal apoptosis, improves 24-hour neurologic deficit scores, and enhances survival in CA rats. In vitro, IL-17 A induced A1 polarization and inflammatory cytokine release in astrocytes, effects abolished by IL-17RA blockade.

Conclusion

Our study elucidates the mechanisms underlying CA-induced neuroinflammation and identifies the IL-17 A pathway as a potential therapeutic target for mitigating neurological injury following cardiac arrest.