Zhen Hong, Zhao Lize, Ling Zhangjun, Kuo Li, Xue Xiarui, Feng Jiaxiu
No. 2 Department of Neurology, Cangzhou Central Hospital, No. 16 Xinhua Western Road, Cangzhou City, Hebei Province, China.
No. 2 Department of Neurology, Cangzhou Central Hospital, No. 16 Xinhua Western Road, Cangzhou City, Hebei Province, China.
Mol Immunol. 2018 Jan;93:31-37. doi: 10.1016/j.molimm.2017.09.020. Epub 2017 Nov 9.
The blood brain barrier (BBB) is a diffusion barrier that maintains the brain environment. Wip1 is a nuclear phosphatase induced by many factors and involved in various stresses, tumorigenesis, organismal aging, and neurogenesis. Wip1's role in BBB integrity has not been thoroughly investigated. The purpose of the present study was to investigate the effect and mechanism of Wip1 on lipopolysaccharide (LPS)-induced BBB dysfunction and inflammation in an in vitro BBB model. The in vitro BBB model was established by co-culturing human brain-microvascular endothelial cells and human astrocytes and then exposing them to 1μg/ml LPS for 6, 12, 18, 24, and 48h. Wip1 expression was significantly elevated by LPS treatment. Knockdown of Wip1 aggravated the increased permeability and decreased transepithelial electrical resistance, protein expression of ZO-1, and occludin induced by LPS. Wip1 silencing augmented the elevated inflammatory cytokines TNF-α, IL-1β, IL-12, and IL-6 of the BBB induced by LPS, whereas overexpression of Wip1 showed a contrary effect. Sonic hedgehog signaling (SHH) was activated by Wip1 overexpression and inhibited by Wip1 silencing. Additionally, activating or inhibiting the SHH pathway by purmorphamine or cyclopamine, respectively, abolished the Wip1-induced changes in transepithelial electrical resistance and permeability and inflammatory responses in the LPS-injured BBB model. Our results demonstrate that Wip1 may protect the BBB against LPS-induced integrity disruption and inflammatory response through the SHH signaling pathway.
血脑屏障（BBB）是一种维持脑内环境的扩散屏障。Wip1是一种由多种因素诱导的核磷酸酶，参与各种应激、肿瘤发生、机体衰老和神经发生过程。Wip1在血脑屏障完整性方面的作用尚未得到充分研究。本研究的目的是在体外血脑屏障模型中研究Wip1对脂多糖（LPS）诱导的血脑屏障功能障碍和炎症的影响及机制。通过将人脑微血管内皮细胞和人星形胶质细胞共培养，然后将它们暴露于1μg/ml LPS中6、12、18、24和48小时，建立体外血脑屏障模型。LPS处理显著提高了Wip1的表达。敲低Wip1会加重LPS诱导的通透性增加、跨上皮电阻降低、ZO-1和闭合蛋白的蛋白表达降低。Wip1沉默增强了LPS诱导的血脑屏障炎症细胞因子TNF-α、IL-1β、IL-12和IL-6的升高，而Wip1过表达则显示出相反的效果。Wip1过表达激活了音猬因子信号通路（SHH），而Wip1沉默则抑制了该通路。此外，分别用嘌呤胺或环杷明激活或抑制SHH通路，消除了Wip-1诱导的LPS损伤血脑屏障模型中跨上皮电阻和通透性的变化以及炎症反应。我们的结果表明，Wip1可能通过SHH信号通路保护血脑屏障免受LPS诱导的完整性破坏和炎症反应。
