TAK1 is essential for endothelial barrier maintenance and repair after lung vascular injury

TGF-beta-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 beta-catenin (beta-cat) and VE-cadherin at endothelial adherens junctions and augmented proteaseactivated 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 (TAK1i.EC) mice, we observed that the lung endothelial barrier was compromised and in addition, TAK1i.EC mice exhibited heightened sensitivity to septic shock. Consistent with these findings, we observed dramatically reduced beta-cat expression in lung ECs of TAK1i.EC mice. Further, either inhibition or knockdown of TAK1 blocked PAR-1- or TLR-4-induced inactivation of glycogen synthase kinase 3 beta (GSK3 beta), which in turn increased phosphorylation, ubiquitylation, and degradation of beta-cat in ECs to destabilize the endothelial barrier. Importantly, we showed that TAK1 inactivates GSK3 beta through AKT activation in ECs. Thus our findings in this study point to the potential of targeting the TAK1-AKT-GSK3 beta axis as a therapeutic approach to treat uncontrolled lung vascular leak during sepsis.