Endothelial septin 4 reduction contributes to lipopolysaccharide-induced acute lung injury by disrupting endothelial barrier integrity and promoting infiltration of ISG+ cells.

The reorganization of endothelial cell (EC) cytoskeletons is linked to increased vascular permeability, a key factor in acute lung injury (ALI). The role of septins (SEPTs), a distinct group of cytoskeletal proteins, in ALI is unknown. This study aims to clarify the roles and mechanisms of endothelial-specific SEPTs in ALI. Pulmonary histology, cell junction proteins, and levels of SEPTs after lipopolysaccharide (LPS) treatment were evaluated. The distribution of SEPTs in lung cells and other organs was analyzed by using scRNA-seq data. SEPT4's impact on endothelial barrier integrity and ALI were assessed by endothelial-specific SEPT4 conditional knockout mice combined with scRNA-seq analysis. We found that LPS-treated mice had significant lung injury and disrupted endothelial barrier integrity, and various SEPTs mRNA and protein levels decreased. SEPT4 was mainly located in ECs and fibroblasts in murine and human tissues. Endothelial SEPT4 knockout compromised pulmonary endothelial barrier integrity, worsened LPS-induced lung injury, promoted interferon-stimulated gene (ISG)+ cell infiltration, inhibited protective and anti-inflammatory responses, and intensified the inflammatory response in lung cells. Conclusively, SEPT4 is selectively distributed in ECs and fibroblasts. Its reduction impairs endothelial barrier integrity, allows ISG+ cell infiltration, and contributes to ALI development. Therefore, SEPT4 represents a potential therapeutic target for ALI.