Department of Pharmacology and Regenerative Medicine, College of Medicine, University of Illinois, Chicago, IL 60612.
Mol Biol Cell. 2022 Jun 1;33(7):ar65. doi: 10.1091/mbc.E21-11-0563. Epub 2022 Mar 24.
TGF-β-activated kinase 1 (TAK1) plays crucial roles in innate and adaptive immune responses and is required for embryonic vascular development. However, TAK1's role in regulating vascular barrier integrity is not well defined. Here we show that endothelial TAK1 kinase function is required to maintain and repair the injured lung endothelial barrier. We observed that inhibition of TAK1 with 5Z-7-oxozeaenol markedly reduced expression of β-catenin (β-cat) and VE-cadherin at endothelial adherens junctions and augmented protease-activated receptor-1 (PAR-1)- or toll-like receptor-4 (TLR-4)-induced increases in lung vascular permeability. In inducible endothelial cell (EC)-restricted TAK1 knockout () mice, we observed that the lung endothelial barrier was compromised and in addition, mice exhibited heightened sensitivity to septic shock. Consistent with these findings, we observed dramatically reduced β-cat expression in lung ECs of mice. Further, either inhibition or knockdown of TAK1 blocked PAR-1- or TLR-4-induced inactivation of glycogen synthase kinase 3β (GSK3β), which in turn increased phosphorylation, ubiquitylation, and degradation of β-cat in ECs to destabilize the endothelial barrier. Importantly, we showed that TAK1 inactivates GSK3β through AKT activation in ECs. Thus our findings in this study point to the potential of targeting the TAK1-AKT-GSK3β axis as a therapeutic approach to treat uncontrolled lung vascular leak during sepsis.
TGF-β 激活激酶 1（TAK1）在先天和适应性免疫反应中发挥着关键作用，是胚胎血管发育所必需的。然而，TAK1 在调节血管屏障完整性方面的作用尚未得到明确界定。在这里，我们表明内皮细胞 TAK1 激酶功能对于维持和修复受损的肺内皮屏障是必需的。我们观察到，用 5Z-7-氧杂豆醇抑制 TAK1，内皮细胞黏附连接处的β-连环蛋白（β-cat）和血管内皮钙黏蛋白（VE-cadherin）的表达显著减少，并增强蛋白酶激活受体-1（PAR-1）或 Toll 样受体-4（TLR-4）诱导的肺血管通透性增加。在诱导型内皮细胞（EC）特异性 TAK1 敲除（）小鼠中，我们观察到肺内皮屏障受损，此外，还观察到这些小鼠对感染性休克的敏感性增加。与这些发现一致，我们观察到这些小鼠的肺 EC 中β-cat 的表达明显减少。此外，抑制或敲低 TAK1 均可阻断 PAR-1 或 TLR-4 诱导的糖原合酶激酶 3β（GSK3β）失活，进而增加 EC 中β-cat 的磷酸化、泛素化和降解，使内皮屏障不稳定。重要的是，我们表明 TAK1 通过 AKT 在 EC 中激活来使 GSK3β 失活。因此，我们在这项研究中的发现表明，靶向 TAK1-AKT-GSK3β 轴可能是治疗脓毒症期间失控性肺血管渗漏的一种治疗方法。
