Gasdermin D protects against noninfectious liver injury by regulating apoptosis and necroptosis

Gasdermin D (GsdmD) was recently identified as the executioner of pyroptotic inflammatory cell death, and is a substrate for caspases-1 and 11. GsdmD is detrimental in lethal endotoxemia but protective in bacterial sepsis. However, little is known about its role during noninfectious/sterile injuries. In this study, we examined the contribution of GsdmD using WT and GsdmD(−/−) mice in two models of noninfectious liver injury: hemorrhagic shock with resuscitation (HS/R) and acetaminophen (APAP) overdose. GsdmD(−/−) mice had significantly increased liver damage at 6 h after HS/R or APAP vs WT, shown by significantly elevated ALT level and extended areas of cell death in liver. Caspase-8, a mediator of multiple cell death pathways, was highly elevated in GsdmD(−/−) mice after injury. Significantly increased cleavage of caspase-8 and subsequent high levels of apoptosis were found in livers of GsdmD(−/−) mice after HS/R, a relatively mild ROS-induced liver injury. However, during more severe APAP-mediated ROS-induced liver injury, caspase-8 cleavage in GsdmD(−/−) liver was inhibited compared with WT, resulting in accumulation of pro-caspase-8 and increased levels of necroptosis. Our findings indicate a novel hepatoprotective role for GsdmD in noninfectious inflammation models via regulation of caspase-8 expression and downstream cell death pathways. The effects of GsdmD protection are likely injury specific and may also depend on injury severity and levels of ROS produced. These data suggest modulation of GsdmD/caspase-8 may be a novel therapeutic option in ROS-mediated liver injury.