Spleen Tyrosine Kinase phosphorylates VE-cadherin to cause endothelial barrier disruption in acute lung injury

• Published in: The Journal of biological chemistry Vol. 299; no. 12; p. 105408
• Main Authors: Shadab, Mohammad, Slavin, Spencer A., Mahamed, Zahra, Millar, Michelle W., Najar, Rauf A., Leonard, Antony, Pietropaoli, Anthony, Dean, David A., Fazal, Fabeha, Rahman, Arshad
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2023; American Society for Biochemistry and Molecular Biology
• Subjects: Acute Lung Injury - metabolism; Acute Lung Injury - pathology; Animals; Antigens, CD - metabolism; Cadherins - metabolism; Capillary Permeability; endothelial cells; Lung - metabolism; lung vascular leak; Mice; Phosphorylation; Respiratory Distress Syndrome; sepsis; Sepsis - complications; Syk; Syk Kinase - metabolism; VE-cadherin; LMVEC; TER; endothelial cells; EBM2; EBA; CLP; HRP; ICAM-1; HPAEC; VE-PTP; MPO; LPS; VE-cadherin; ARDS; EC; Syk; TBS; VEGF; ECIS; AJs; ECL; lung vascular leak; EV; VCAM-1; pCMV-cre; DEAE; Syk-KD; sepsis; ALI; DDAB
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1016/j.jbc.2023.105408

Increased endothelial cell (EC) permeability is a cardinal feature of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Tyrosine phosphorylation of VE-cadherin is a key determinant of EC barrier disruption. However, the identity and role of tyrosine kinases in this context are incompletely understood. Here we report that Spleen Tyrosine Kinase (Syk) is a key mediator of EC barrier disruption and lung vascular leak in sepsis. Inhibition of Syk by pharmacological or genetic approaches, each reduced thrombin-induced EC permeability. Mechanistically, Syk associates with and phosphorylates VE-cadherin to cause EC permeability. To study the causal role of endothelial Syk in sepsis-induced ALI, we used a remarkably efficient and cost-effective approach based on gene transfer to generate EC-ablated Syk mice. These mice were protected against sepsis-induced loss of VE-cadherin and inflammatory lung injury. Notably, the administration of Syk inhibitor R788 (fostamatinib); currently in phase II clinical trial for the treatment of COVID-19, mitigated lung injury and mortality in mice with sepsis. These data identify Syk as a novel kinase for VE-cadherin and a druggable target against ALI in sepsis.