The Polo-Like Kinase 1-Mammalian Target of Rapamycin Axis Regulates Autophagy to Prevent Intestinal Barrier Dysfunction During Sepsis
The Polo-Like Kinase 1-Mammalian Target of Rapamycin Axis Regulates Autophagy to Prevent Intestinal Barrier Dysfunction During Sepsis
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DOI：
10.1016/j.ajpath.2022.11.008
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发表时间：
2023-02-28
影响因子：
6
通讯作者：
Lu, Wei-Hua
中科院分区：
文献类型：
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作者：
Cao, Ying-Ya;Qiao, Yang;Lu, Wei-Hua
肠道在脓毒症的发展中起着至关重要的作用。肠上皮细胞自噬和凋亡之间的平衡是动态的，并决定肠通透性。本研究主要探讨自噬在脓毒症诱导的肠道屏障功能障碍中的潜在作用，并探讨其体内和体外机制。脓毒症小鼠肠上皮细胞过度凋亡，肠屏障被破坏。雷帕霉素促进自噬可减少肠上皮细胞凋亡，恢复肠屏障功能，表现为血清二胺氧化酶（DAO）和异硫氰酸酯-葡聚糖40 （FD40）水平降低，Occludin -1 （ZO-1）和Occludin表达增加。小鼠polo样激酶1 （PLK1）敲低可改善脓毒症期间肠道上皮细胞凋亡和肠道屏障，而氯喹可降低这些作用，雷帕霉素可增强这些作用。PLK1还能促进细胞自噬，改善脂多糖诱导的细胞凋亡和高通透性。此外，PLK1在脓毒症期间与哺乳动物雷帕霉素靶蛋白（mTOR）发生物理相互作用，并参与肠上皮细胞的相互调节串扰。该研究为自噬在脓毒症诱导的肠屏障功能障碍中的作用提供了新的见解，并表明PLK1-mTOR轴可能是脓毒症的一个有希望的治疗靶点。
The intestines play a crucial role in the development of sepsis. The balance between autophagy and apoptosis in intestinal epithelial cells is dynamic and determines intestinal permeability. The present study focused on the potential role of autophagy in sepsis-induced intestinal barrier dysfunction and explored the mechanisms in vivo and in vitro. Excessive apoptosis in intestinal epithelia and a disrupted intestinal barrier were observed in septic mice. Promoting autophagy with rapamycin reduced intestinal epithelial apoptosis and restored intestinal barrier function, presenting as decreased serum diamine oxidase (DAO) and fluorescein isothiocyanate-dextran 40 (FD40) levels and increased expression of zonula occludens-1 (ZO-1) and Occludin. Polo-like kinase 1 (PLK1) knockdown in mice ameliorated in-testinal epithelial apoptosis and the intestinal barrier during sepsis, whereas these effects were reduced with chloroquine and enhanced with rapamycin. PLK1 also promoted cell autophagy and improved lipopolysaccharide-induced apoptosis and high permeability in vitro. Moreover, PLK1 physically interacted with mammalian target of rapamycin (mTOR) and participated in reciprocal regulatory crosstalk in in-testinal epithelial cells during sepsis. This study provides novel insight into the role of autophagy in sepsis-induced intestinal barrier dysfunction and indicates that the PLK1-mTOR axis may be a promising therapeutic target for sepsis.