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Vascular endothelial cadherin (VE-cad) expression at endothelial adherens junctions (AJs) regulates vascular homeostasis. Here we show that endothelial A20 is required for VE-cad expression at AJs to maintain and repair the injured endothelial barrier. In endothelial cell (EC)-restricted  Tnfaip3  (A20) knockout ( A20   ∆EC  ) mice, LPS challenge caused uncontrolled lung vascular leak and persistent sequestration of polymorphonuclear neutrophil (PMNs). Importantly,  A20   ∆EC   mice exhibited drastically reduced VE-cad expression in lungs compared with wild-type counterparts. Endothelial expression of wild-type A20 but not the deubiquitinase-inactive A20 mutant (A20 C103A ) prevented VE-cad ubiquitination, restored VE-cad expression, and suppressed lung vascular leak in  A20   ∆EC   mice. Interestingly, IRAK-M-mediated nuclear factor-κB (NF-κB) signaling downstream of TLR4 was required for A20 expression in ECs. interleukin-1 receptor-associated kinase M (IRAK-M) knockdown suppressed basal and LPS-induced A20 expression in ECs. Further, in vivo silencing of IRAK-M in mouse lung vascular ECs through the CRISPR-Cas9 system prevented expression of A20 and VE-cad while augmenting lung vascular leak. These results suggest that targeting of endothelial A20 is a potential therapeutic strategy to restore endothelial barrier integrity in the setting of acute lung injury.

Deubiquitinase function of A20 maintains and repairs endothelial barrier after lung vascular injury