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.Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury
The Journal of Clinical Investigation R E S E A R C H A R T I C L E4 1 2 5 jci.org Volume 127 Number 11 November 2017the complex process of inflammation involves multiple programmed cell death pathways, depending on the type and magnitude of the inciting stimulus and cell type. From an evolutionary perspective, pyroptosis of cells harboring intracellular bacteria or in which LPS has breached the plasma membrane is an effective means of eliminating an intracellular bacterial niche and activating the host through release of inflammatory mediators such as IL-1β, while sparing uninfected neighboring cells (13,(28)(29)(30). Thus, pyroptosis induced by inflammatory caspases 1/4/5/11 is an innate immune response distinct from the canonical inflammasome activation pathway via cell-surface TLR4 (11,(31)(32)(33)(34). However, caspase-11 can also be immunopathologic in sepsis (35). Caspase-11-deficient mice were protected in endotoxemic shock (10,11), suggesting that in the setting of an overwhelming inflammatory response, the potentially protective pyroptotic mechanism activates an exaggerated pathologic response due to overwhelming cell lysis. The role of the inflammatory caspases 4/5/11 in mediating cytoplasmic LPS signaling and pyroptosis has until now been primarily studied in macrophages or dendritic cells (11,12,14,28,32,36). Their role in destroying the endothelial barrier through widespread endothelial death and pathogenesis of ALI remains unknown. Here, we tested the hypothesis that lung ECs are a primary target for pyroptosis via intracellular sensing of LPS by the inflammatory caspases 4/5/11 and that endothelial pyroptosis is required for the induction of ALI.
Results
LPS in ECs induces pyroptotic cell death via activation of inflammatory cas...
