内皮NLRP3焦亡作为慢性间歇性缺氧中血脑屏障破坏和神经毒性星形胶质细胞生成的触发因素

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中文摘要

慢性间歇性缺氧（CIH）是阻塞性睡眠呼吸暂停的标志，可导致认知缺陷，但CIH与神经损伤之间的细胞机制仍不明确。本研究确定内皮焦亡是CIH诱导的神经血管功能障碍的触发因素。通过结合体内CIH动物模型、原代星形胶质细胞培养、内皮细胞系、分子谱分析和行为实验，我们证明CIH特异性激活脑微血管内皮细胞中的NLR家族 pyrin 结构域包含3（NLRP3）炎症小体，最终导致Gasdermin D介导的焦亡以及成熟白细胞介素-1β和白细胞介素-18的释放。来自这些焦亡内皮细胞的条件培养基直接诱导原代星形胶质细胞采用神经毒性A1表型，其特征是补体成分3的上调。这种A1转化反过来损害内皮屏障完整性，表现为claudin-5表达减少。内皮细胞中NLRP3的基因敲低或体内用MCC950抑制可抑制焦亡，减弱A1星形胶质细胞活化，保留血脑屏障功能，并挽救CIH相关的空间记忆障碍。我们的发现确立了内皮NLRP3依赖性焦亡作为驱动星形胶质细胞适应不良的必要上游机制，后者反过来主动破坏血脑屏障完整性，突出了减轻缺氧性疾病认知衰退的关键靶点。

英文摘要

Chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnea, leads to cognitive deficits, yet the cellular mechanisms between CIH and neural injury remain poorly defined. This study identifies endothelial pyroptosis as a trigger in CIH-induced neurovascular dysfunction. Using a combination of in vivo CIH animal modeling, primary astrocyte culture, endothelial cell line, molecular profiling, and behavioral experiments, we demonstrate that CIH specifically activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome in brain microvascular endothelial cells, culminating in Gasdermin D-mediated pyroptosis and the release of mature interleukin‑1β and interleukin‑18. Conditioned medium from these pyroptotic endothelial cells directly induced primary astrocytes to adopt a neurotoxic A1 phenotype, characterized by upregulation of complement component 3. This A1 transformation, in turn, compromised endothelial barrier integrity, evidenced by reduced claudin-5 expression. Genetic knockdown of NLRP3 in endothelial cells or inhibition with MCC950 in vivo suppressed pyroptosis, blunted A1 astrocyte activation, preserved blood-brain barrier function, and rescued CIH-associated spatial memory impairments. Our findings establish endothelial NLRP3-dependent pyroptosis as a necessary upstream mechanism that drives astrocytic maladaptation, which in turn actively disrupts blood-brain barrier integrity, highlighting a pivotal target for mitigating cognitive decline in hypoxic disorders.