Lipocalin 10 is essential for protection against inflammation-triggered vascular leakage by activating LRP2-Ssh1 signaling pathway.

AIMS: Systemic inflammation occurs commonly during many human disease settings and increases vascular permeability, leading to organ failure and lethal outcomes. Lipocalin 10 (Lcn10), a poorly characterized member of the lipocalin family, is remarkably altered in the cardiovascular system of human patients with inflammatory conditions. Nonetheless, whether Lcn10 regulates inflammation-induced endothelial permeability remains unknown.

METHODS AND RESULTS: Systemic inflammation models were induced using mice by injection of endotoxin LPS or cecal ligation and puncture (CLP) surgery. We observed that the expression Lcn10 was dynamically altered only in endothelial cells (ECs), but not in either fibroblasts or cardiomyocytes isolated from mouse hearts following LPS challenge or CLP surgery. Using in vitro gain- and loss-of-function approaches and an in vivo global knockout (KO) mouse model, we discovered that Lcn10 negatively regulated endothelial permeability upon inflammatory stimuli. Loss of Lcn10 augmented vascular leakage, leading to severe organ damage and higher mortality following LPS challenge, compared to wild-type (WT) controls. By contrast, overexpression of Lcn10 in ECs displayed opposite effects. A mechanistic analysis revealed that both endogenous and exogenous elevation of Lcn10 in ECs could activate slingshot homolog 1 (Ssh1)-Cofilin signaling cascade, a key axis known to control actin filament dynamics. Accordingly, a reduced formation of stress fiber and increased generation of cortical actin band were exhibited in Lcn10-ECs, when compared to controls upon endotoxin insults. Furthermore, we identified that Lcn10 interacted with LDL receptor-related protein 2 (LRP2) in ECs, which acted as an upstream factor of the Ssh1-Confilin signaling. Lastly, injection of recombinant Lcn10 protein into endotoxic mice showed therapeutic effects against inflammation-induced vascular leakage.

CONCLUSION: This study identifies Lcn10 as a novel regulator of EC function and illustrates a new link in the Lcn10-LRP2-Ssh1 axis to controlling endothelial barrier integrity. Our findings may provide novel strategies for the treatment of inflammation-related diseases.