Zhao Ruixue, Ma Yajun, Li Shujuan, Li Junfa
Department of Neurobiology, School of Basic Medical Science, Capital Medical University, Beijing 100069, China.
The Neurological Department, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100037, China.
Biomolecules. 2025 Aug 6;15(8):1134. doi: 10.3390/biom15081134.
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. Utilizing a rat CPB model and an oxygen-glucose deprivation/reoxygenation (OGD/R) cellular model, we demonstrated that IL-17A levels were markedly elevated in the hippocampus post-CPB, correlating with endoplasmic reticulum stress (ERS)-mediated apoptosis. Transcriptomic analysis revealed the enrichment of IL-17 signaling and apoptosis-related pathways. IL-17A-Neutralizing monoclonal antibody (mAb) and the ERS inhibitor 4-phenylbutyric acid (4-PBA) significantly attenuated neurological deficits and hippocampal neuronal damage. Mechanistically, IL-17A activated the Act1-IRE1-JNK1 axis, wherein heat shock protein 90 (Hsp90) competitively regulated Act1-IRE1 interactions. Co-immunoprecipitation confirmed the enhanced Hsp90-Act1 binding post-CPB, promoting IRE1 phosphorylation and downstream caspase-12 activation. In vitro, IL-17A exacerbated OGD/R-induced apoptosis via IRE1-JNK1 signaling, reversible by IRE1 inhibition. 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.
体外循环（CPB）与严重的神经并发症相关，但脑损伤的潜在机制仍不清楚。本研究调查了白细胞介素-17A（IL-17A）在加重CPB诱导的神经元凋亡中的作用，并确定了易损脑区。利用大鼠CPB模型和氧糖剥夺/复氧（OGD/R）细胞模型，我们证明CPB后海马中IL-17A水平显著升高，与内质网应激（ERS）介导的凋亡相关。转录组分析揭示了IL-17信号通路和凋亡相关通路的富集。IL-17A中和单克隆抗体（mAb）和ERS抑制剂4-苯基丁酸（4-PBA）显著减轻神经功能缺损和海马神经元损伤。机制上，IL-17A激活了Act1-IRE1-JNK1轴，其中热休克蛋白90（Hsp90）竞争性调节Act1-IRE1相互作用。免疫共沉淀证实CPB后Hsp90-Act1结合增强，促进IRE1磷酸化和下游caspase-12激活。在体外，IL-17A通过IRE1-JNK1信号通路加重OGD/R诱导的凋亡，IRE1抑制可使其逆转。这些发现确定海马是关键的易损区域，并描绘了一条驱动ERS依赖性凋亡的新的IL-17A/Act1-IRE1-JNK1通路。靶向IL-17A或Hsp90介导的伴侣蛋白转换是CPB相关神经保护的一种有前景的治疗策略。本研究为心脏手术期间全身炎症与神经元应激反应之间的分子相互作用提供了重要见解。
