Brain endothelial GSDMD activation mediates inflammatory BBB breakdown

• 成果类型: Article
• 署名作者: Wei, Chao; Jiang, Wei; Wang, Ruiyu; Zhong, Haoyu; He, Huabin; Gao, Xinwei; Zhong, Shilin; Yu, Fengting; Guo, Qingchun; Zhang, Li; Schiffelers, Lisa D. J.; Zhou, Bin; Trepel, Martin; Schmidt, Florian I.; Luo, Minmin; Shao, Feng
• 署名单位: Chinese Institute for Brain Research, Beijing; National Institute of Biological Sciences, Beijing; Chinese Academy of Medical Sciences - Peking Union Medical College; University of Bonn; Chinese Academy of Sciences; Center for Excellence in Molecular Cell Science, CAS; Chinese Academy of Medical Sciences - Peking Union Medical College; Tsinghua University; Changping Laboratory
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4412
• DOI: 10.1038/s41586-024-07314-2
• 发表日期: 2024-05-23
• 关键词: transcriptomic cell-types; lps; caspases; taxonomy; barrier; adult

摘要

The blood-brain barrier (BBB) protects the central nervous system from infections or harmful substances(1); its impairment can lead to or exacerbate various diseases of the central nervous system(2-4). However, the mechanisms of BBB disruption during infection and inflammatory conditions(5,6) remain poorly defined. Here we find that activation of the pore-forming protein GSDMD by the cytosolic lipopolysaccharide (LPS) sensor caspase-11 (refs. (7-9)), but not by TLR4-induced cytokines, mediates BBB breakdown in response to circulating LPS or during LPS-induced sepsis. Mice deficient in the LBP-CD14 LPS transfer and internalization pathway(10-12) resist BBB disruption. Single-cell RNA-sequencing analysis reveals that brain endothelial cells (bECs), which express high levels of GSDMD, have a prominent response to circulating LPS. LPS acting on bECs primes Casp11 and Cd14 expression and induces GSDMD-mediated plasma membrane permeabilization and pyroptosis in vitro and in mice. Electron microscopy shows that this features ultrastructural changes in the disrupted BBB, including pyroptotic endothelia, abnormal appearance of tight junctions and vasculature detachment from the basement membrane. Comprehensive mouse genetic analyses, combined with a bEC-targeting adeno-associated virus system, establish that GSDMD activation in bECs underlies BBB disruption by LPS. Delivery of active GSDMD into bECs bypasses LPS stimulation and opens the BBB. In CASP4-humanized mice, Gram-negative Klebsiella pneumoniae infection disrupts the BBB; this is blocked by expression of a GSDMD-neutralizing nanobody in bECs. Our findings outline a mechanism for inflammatory BBB breakdown, and suggest potential therapies for diseases of the central nervous system associated with BBB impairment.