Cardiopulmonary bypass-induced IL-17A aggravates Caspase-12 dependent neuronal apoptosis through the Act1-IRE1-JNK1 Pathway

Background: Cardiopulmonary bypass (CPB) is associated with significant neurological complications, yet the mechanisms underlying brain injury remain unclear. This study investigated the role of interleukin-17A (IL-17A) in exacerbating CPB-induced neuronal apoptosis and identified vulnerable brain regions. Methods: Utilizing a rat CPB model and an oxygen-glucose deprivation/reoxygenation (OGD/R) cellular model, we assessed IL-17A levels and their correlation with endoplasmic reticulum stress (ERS)-mediated apoptosis. Transcriptomic analysis was performed to identify enriched pathways. The effects of IL-17A-neutralizing monoclonal antibody (mAb) and the ERS inhibitor were evaluated. Results: IL-17A levels were markedly elevated in the hippocampus post-CPB, correlating with ERS-mediated apoptosis. Transcriptomics revealed enrichment of IL-17 signaling and apoptosis-related pathways. IL-17A-neutralizing mAb and 4-PBA significantly attenuated neurological deficits and hippocampal neuronal damage. Mechanistically, IL-17A activated the Act1-IRE1-JNK1 axis, with Hsp90 competitively regulating Act1-IRE1 interactions to promote IRE1 phosphorylation and caspase-12 activation. In vitro, IL-17A exacerbated OGD/R-induced apoptosis via Act1-IRE1-JNK1 signaling, which was reversible by IRE1 inhibition. Conclusions: These findings identify the hippocampus as a key vulnerable region and delineate a novel IL-17A/Act1-IRE1-JNK1 pathway driving ERS-dependent apoptosis. Targeting IL-17A or Hsp90-mediated chaperone switching represents a promising therapeutic strategy for CPB-associated neuroprotection. This study provides critical insights into the molecular crosstalk between systemic inflammation and neuronal stress responses during cardiac surgery.