2. Academic Validation
  3. Cardiac arrest triggers IL-17-mediated neuroinflammation and astrocyte polarization: insights into pathogenesis and intervention

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

  • J Neuroinflammation. 2025 Nov 14;22(1):268. doi: 10.1186/s12974-025-03600-6.
Shumei Li # 1 2,  Lei Wang # 3,  Qiqi Luo # 3,  Maiying Fan # 4,  Yixiao Xu 4,  Xiehong Liu 5,  Yiyuan Zhang 1 2,  Lianhong Zou 6 7
Affiliations

Affiliations

  • 1 Institute of Clinical Translational Medicine, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410005, P.R. China.
  • 2 Geriatric Immunization Research Center of Hunan Provincial Geriatric Institute, Changsha, Hunan, 410024, P. R. China.
  • 3 The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, 410005, P.R. China.
  • 4 Department of Emergency Medicine, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410005, P.R. China.
  • 5 Hunan Provincial Key Laboratory of Emergency and Critical Care Metabolomics, Changsha, Hunan, 410005, P.R. China.
  • 6 Institute of Clinical Translational Medicine, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410005, P.R. China. [email protected].
  • 7 Geriatric Immunization Research Center of Hunan Provincial Geriatric Institute, Changsha, Hunan, 410024, P. R. China. [email protected].
  • # Contributed equally.
PMID: 41239323 DOI: 10.1186/s12974-025-03600-6
Abstract

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.

Keywords

Astrocyte polarization; Blood–brain barrier; Cardiac arrest; IL-17A; Neuroinflammation; Th17 cells.

Figures
Products
Inhibitors & Agonists