Glycyrrhizin attenuates caspase-11-dependent immune responses and coagulopathy by targeting high mobility group box 1

Caspase-11, a cytosolic endotoxin (lipopolysaccharide: LPS) receptor, mediates pyroptosis, coagulopathy and lethality in endoxemia and bacterial sepsis. The activation of caspase-11 requires high mobility group box 1 (HMGB1)-mediated translocation of LPS from the extracellular space to the cytosol. Here we show that HMGB1dependent cytosolic delivery of LPS was blocked by glycyrrhizin, a medication to treat liver diseases. Glycyrrhizin competitively bound HMGB1 and thereby inhibiting the physical interaction between HMGB1 and LPS. Treatment of glycyrrhizin significantly attenuated caspase-11-dependent immune responses, coagulopathy, organ injury and lethality in endotoxemia and experimental sepsis. Together, our data suggest that pharmacological inhibition of the cytosolic delivery of LPS by glycyrrhizin might be a potential therapeutic strategy to treat sepsis, which is a leading cause of death in hospitals worldwide.

Automated summary

This study found that glycyrrhizin can block cytosolic delivery of LPS mediated by HMGB1, thereby attenuating the inflammatory response, coagulopathy, organ injury, and death caused by endotoxemia and sepsis. This finding suggests that pharmacological inhibition of cytosolic delivery of LPS may be a potential therapeutic strategy for treating sepsis.