Endothelial Cell Deubiquitinase A20 Signals Repair of Lung Vascular Injury

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 DESCRIPTION (provided by applicant): Acute lung injury (ALI) is a complex inflammatory disease associated with increased lung vascular permeability and formation of protein-rich edema fluid and an infiltration of inflammatory cells in lung tissue and airspace. Reassembly of lung vascular endothelial adherens junctions (AJs) is a critical factor contributing to resolution f acute inflammatory lung injury. Expression of vascular endothelial (VE)-cadherin and the interacting endothelial protein tyrosine phosphatase (VE-PTP) at AJs is vital for endothelial barrier integrity. However, the signaling mechanisms that mediate the reassembly of endothelial AJs are poorly understood. We have identified in a genetic model of endothelial cell (EC)-restricted A20 (Tnfaip3) knockout (A20ΔEC) mice, the novel role of the ubiquitin editing function of A20 in regulating expression of VE-cadherin and VE-PTP at AJs. We made the following key observations (Supporting Data): (i) A20ΔEC mice displayed markedly reduced expression of VE- cadherin and VE-PTP at AJs; (ii) VE-cadherin and VE-PTP expression was not restored at AJs of A20ΔEC mice after endotoxin challenge; (iii) A20ΔEC mice showed persistent prolyl hydroxylase 2 (PHD2) expression and defective HIF2α expression post-endotoxin challenge. Based on these novel observations, in Aim 1, we will test the hypothesis that expression of A20 in lung ECs, downstream of TLR4 signaling, promotes the sequestration of VE-cadherin at AJs, and thus is a central feedback mechanism for stabilizing endothelial barrier and promoting resolution of lung injury. In Aim 2, we will test the hypothesis that EC-expressed A20 serves a pro-resolution function in inflammatory lung injury by down-regulating PHD2 to stabilize HIF2α and transcriptionally regulating VE-PTP expression so as to strengthen VE-cadherin function at AJs. With a better understanding of the signaling mechanisms of A20 function in lung endothelial cells, we will be in a position to identify therapeutic strategies that can target A20 function and thereby restore endothelial barrier integrity to resolve inflammatory lung injury.