PLK1 protects intestinal barrier function during sepsis by targeting mitochondrial dynamics through TANK-NF-κB signalling.
PLK1 protects intestinal barrier function during sepsis by targeting mitochondrial dynamics through TANK-NF-κB signalling.
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DOI：
10.1186/s10020-022-00597-z
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发表时间：
2022-12-29
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肠道屏障的完整性在脓毒症的发病机制中至关重要。尽管有大量的证据，但肠屏障在脓毒症病理中的分子机制仍不清楚。在这里，我们报道了polo样激酶1 （PLK1）在脓毒症期间肠屏障完整性中的保护作用。PLK1过表达小鼠（CAG-PLK1小鼠）或PLK1抑制小鼠（bi2536处理小鼠）采用盲肠结扎穿刺（CLP）建立脓毒症模型。观察肠屏障功能、肠上皮细胞凋亡、线粒体功能及NF-κB信号转导活性。为了抑制NF-κB信号的激活，给予NF-κB抑制剂PDTC。选择Caco-2细胞系建立体外肠上皮损伤模型。脓毒症破坏肠道屏障功能，诱导肠上皮过度凋亡，破坏野生型小鼠线粒体动力学平衡。PLK1过表达通过抑制NF-κB信号的激活，减轻脓毒症诱导的肠上皮损伤。PLK1在Caco-2细胞中与TANK共定位并相互作用。用TANK-SiRNA转染Caco-2细胞可抑制NF-κB信号传导，改善脂多糖（LPS）诱导的线粒体功能障碍、细胞凋亡和细胞高通透性。此外，TANK过表达削弱了PLK1对lps诱导的Caco-2细胞损伤的保护作用。我们的研究结果表明，PLK1/TANK/NF-κB轴通过调节肠上皮细胞的线粒体动力学和凋亡，在脓毒症诱导的肠屏障功能障碍中起着至关重要的作用，可能是临床潜在的治疗靶点。在线版本包含补充材料，可在10.1186/s10020-022-00597-z获得。
Intestinal barrier integrity in the pathogenesis of sepsis is critical. Despite an abundance of evidence, the molecular mechanism of the intestinal barrier in sepsis pathology remains unclear. Here, we report a protective role of polo-like kinase 1 (PLK1) in intestinal barrier integrity during sepsis. Mice with PLK1 overexpression (CAG-PLK1 mice) or PLK1 inhibition (BI2536-treated mice) underwent caecal ligation and puncture (CLP) to establish a sepsis model. The intestinal barrier function, apoptosis in the intestinal epithelium, mitochondrial function and NF-κB signalling activity were evaluated. To suppress the activation of NF-κB signalling, the NF-κB inhibitor PDTC, was administered. The Caco-2 cell line was chosen to establish an intestinal epithelial injury model in vitro. Sepsis destroyed intestinal barrier function, induced excessive apoptosis in the intestinal epithelium, and disrupted the balance of mitochondrial dynamics in wild-type mice. PLK1 overexpression alleviated sepsis-induced damage to the intestinal epithelium by inhibiting the activation of NF-κB signalling. PLK1 colocalized and interacted with TANK in Caco-2 cells. Transfecting Caco-2 cells with TANK-SiRNA suppressed NF-κB signalling and ameliorated mitochondrial dysfunction, apoptosis and the high permeability of cells induced by lipopolysaccharide (LPS). Furthermore, TANK overexpression impaired the protective effect of PLK1 on LPS-induced injuries in Caco-2 cells. Our findings reveal that the PLK1/TANK/NF-κB axis plays a crucial role in sepsis-induced intestinal barrier dysfunction by regulating mitochondrial dynamics and apoptosis in the intestinal epithelium and might be a potential therapeutic target in the clinic. The online version contains supplementary material available at 10.1186/s10020-022-00597-z.
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