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

IntroductionCardiac 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.ObjectiveTo 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.