Caspase-11–mediated endothelial pyroptosis underlies endotoxemia-induced lung injury

TLDR

Acute lung injury, a leading cause of death in bacterial sepsis, arises from widespread destruction of the lung endothelial barrier, producing protein‑rich edema, leukocyte influx, and hypoxemia, yet the role of pyroptosis in endothelial cell death remains poorly understood. Systemic LPS induces endothelial pyroptosis through caspase‑11 (human caspases 4/5), and mice lacking caspase‑11 or with endothelial‑specific deletion of this caspase exhibit markedly reduced lung edema, neutrophil infiltration, and mortality, establishing endothelial pyroptosis as a key driver of endotoxemia‑induced lung injury and a potential therapeutic target.

Abstract

Acute lung injury is a leading cause of death in bacterial sepsis due to the wholesale destruction of the lung endothelial barrier, which results in protein-rich lung edema, influx of proinflammatory leukocytes, and intractable hypoxemia. Pyroptosis is a form of programmed lytic cell death that is triggered by inflammatory caspases, but little is known about its role in EC death and acute lung injury. Here, we show that systemic exposure to the bacterial endotoxin lipopolysaccharide (LPS) causes severe endothelial pyroptosis that is mediated by the inflammatory caspases, human caspases 4/5 in human ECs, or the murine homolog caspase-11 in mice in vivo. In caspase-11-deficient mice, BM transplantation with WT hematopoietic cells did not abrogate endotoxemia-induced acute lung injury, indicating a central role for nonhematopoietic caspase-11 in endotoxemia. Additionally, conditional deletion of caspase-11 in ECs reduced endotoxemia-induced lung edema, neutrophil accumulation, and death. These results establish the requisite role of endothelial pyroptosis in endotoxemic tissue injury and suggest that endothelial inflammatory caspases are an important therapeutic target for acute lung injury.