北京生命科学研究所邵峰团队与北京脑科学与类脑研究所罗敏敏团队合作，探明了脑内皮GSDMD激活介导炎症性血脑屏障破坏。2024年4月17日，国际知名学术期刊《自然》发表了这一成果。

据介绍，血脑屏障(BBB)保护中枢神经系统免受感染或有害物质的侵害，它的损伤可导致或加重中枢神经系统的各种疾病。然而，在感染和炎症条件下血脑屏障破坏的机制仍不清楚。

研究人员发现胞质脂多糖(LPS)传感因子caspase-11激活打孔蛋白GSDMD，但不通过TLR4诱导的细胞因子，在循环系统LPS或LPS诱导的败血症中介导血脑屏障破坏。缺乏LBP-CD14脂多糖转移和内化途径的小鼠可抵抗血脑屏障破坏。单细胞RNA测序分析显示，表达高水平GSDMD的脑内皮细胞(bECs)对循环LPS有显著的反应。LPS作用于bECs，启动Casp11和Cd14的表达，诱导GSDMD介导的质膜通透性和小鼠焦亡。

电镜显示，破坏的血脑屏障发生超微结构改变，包括内皮细胞焦亡，紧密连接异常，血管脱离基底膜。综合小鼠基因组遗传分析，结合针对bECs的腺相关病毒系统，证实了GSDMD在bECs中的激活是脂多糖破坏血脑屏障的基础。向bECs输送活性GSDMD绕过LPS刺激，能够打开血脑屏障。在CASP4人源化小鼠中，革兰氏阴性肺炎克雷伯菌感染破坏血脑屏障，这是通过在bECs中表达GSDMD中和纳米体来阻断的。他们的发现概述了炎症性血脑屏障破坏的机制，并提出了与血脑屏障损伤相关的中枢神经系统疾病的潜在治疗方法。

附：英文原文

Title: Brain endothelial GSDMD activation mediates inflammatory BBB breakdown

Author: 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

Issue&Volume: 2024-04-17

Abstract: The blood–brain barrier (BBB) protects the central nervous system from infections or harmful substances1; its impairment can lead to or exacerbate various diseases of the central nervous system2,3,4. However, the mechanisms of BBB disruption during infection and inflammatory conditions5,6 remain poorly defined. Here we find that activation of the pore-forming protein GSDMD by the cytosolic lipopolysaccharide (LPS) sensor caspase-11 (refs. 7,8,9), 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 pathway10,11,12 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.

DOI: 10.1038/s41586-024-07314-2

Source: https://www.nature.com/articles/s41586-024-07314-2