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

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. 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. 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. 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. 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. 1. Cardiac arrest drives Th17 cell differentiation and disrupts the blood–brain barrier, enabling IL-17A/F infiltration into the hippocampus. 2. IL-17A/F binding to astrocytic IL-17RA/RC activates NF-κB/MAPK signaling, triggering neurotoxic A1 astrocyte polarization. 3. A1 astrocytes secrete pro-inflammatory cytokines that amplify neuronal apoptosis and worsen neurological outcomes. 4. IL-17RA neutralization reverses A1 polarization, reduces neuroinflammation, and improves survival after cardiac arrest. CA induces Th17 cell differentiation and disrupts the BBB. Th17 cell and their secreted IL-17A/F infiltrates into hippocampus, activates astrocytic IL-17RA/RC, and propagates neurotoxic A1 astrocyte-mediated neuroinflammation. Targeting the IL-17 pathway represents a promising therapeutic strategy to mitigate hippocampal injury and improve neurologic prognosis after CA.