| First Author | Soni D | Year | 2018 |
| Journal | Cell Death Discov | Volume | 4 |
| Pages | 60 | PubMed ID | 29796309 |
| Mgi Jnum | J:280219 | Mgi Id | MGI:6369124 |
| Doi | 10.1038/s41420-018-0056-3 | Citation | Soni D, et al. (2018) Deubiquitinase function of A20 maintains and repairs endothelial barrier after lung vascular injury. Cell Death Discov 4:60 |
| abstractText | 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-kappaB (NF-kappaB) 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. |
