Endothelial NLRP3 pyroptotic as a trigger for blood brain barrier disruption and neurotoxic Astrogenesis in chronic intermittent hypoxia.

Authors

Xia Zihan, Yuqi Yuan, Niu Xiaoxin, Simin Zhu, Jiayi Yang, Rui Lu, Zitong Wang, Chendi Lu, Xie Yushan, Yani Feng, Jiayi Du, Zhang Chutong, Jin Chenxi, Lu Chanchan, Liu Haiqin, Hu Weichao, Erich Gulbins, Xiaoyong Ren, Yewen Shi

Published in

Biochemical pharmacology. Pages 118457. Sep 10, 2026. Epub Sep 10, 2026.

Abstract

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.

PMID:
42722082
Bibliographic data and abstract were imported from PubMed on 11 Sep 2026.

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