Angiopoietin-like 4 protects against sepsis-induced endothelial dysfunction

Endothelial dysfunction plays a central role in sepsis pathogenesis and is recognized as a critical therapeutic target. To date, no effective agent for preserving endothelial integrity is available. Here, using Neisseria meningitidis, a bacterial pathogen that colonizes both peripheral and cerebral microvascular endothelial cells, causing severe form of sepsis and meningitis, we investigated the mechanism occurring at the blood brain barrier level to protect the brain parenchyma from bacteria-induced endothelial dysfunction. We identified Angiopoietin-like 4 as a key factor produced by the brain endothelium that shields the brain barrier from bacterial insult. Conversely, Angiopoietin-like 4 is produced at low level in peripheral endothelium and treatment with Angiopoietin-like 4 efficiently prevented vascular leakage, organ failure and death in murine models of lethal sepsis. Protection was confered by a previously uncharacterized domain within the N-terminal portion of Angiopoietin-like 4 through binding to the heparan proteoglycan Syndecan-4. These findings reveal a novel therapeutic option to efficiently prevent endothelial dysfunction and improve outcomes in patients with sepsis.