Endothelial CLEC5A drives barrier dysfunction and vascular leakage responsible for lung injury in bacterial pneumonia and sepsis.

Summary

Using murine CLP and LPS models, the authors show that endothelial CLEC5A causally drives inflammatory vascular leakage and mortality. Endothelial-specific CLEC5A knockdown improved survival, reversed by endothelial reexpression, and scRNA-seq revealed endothelial transcriptomic heterogeneity in CLEC5A-deficient lungs.

Key Findings

• Clec5a−/− mice exhibited decreased mortality after CLP-induced polymicrobial sepsis and LPS-induced endotoxemia.
• Endothelial-specific CLEC5A knockdown improved survival; endothelial reexpression abrogated this benefit, indicating endothelial causality.
• Single-cell RNA sequencing revealed transcriptomic heterogeneity among vascular endothelial cells in CLEC5A-deficient lungs after CLP.
• Protection was linked to attenuation of the inflammatory cytokine surge and reduced vascular leakage.

Clinical Implications

Therapeutic inhibition of endothelial CLEC5A could reduce vascular leakage and lung injury in bacterial pneumonia and sepsis; biomarker strategies might stratify patients with endothelial activation.

Limitations

• Findings are in murine models; human validation and pharmacologic targeting were not presented.
• The abstract does not detail specific human endothelial data or candidate inhibitors.

Future Directions

Develop selective CLEC5A antagonists or blocking antibodies with endothelial targeting, validate in human tissues and organoids, and assess efficacy in large-animal sepsis models.