The role of inflammasome and caspase-1 in regulating adaptive response to oxidative stress in mouse hepatocytes.

摘要

In myeloid cells, oxidative stress can induce the activation of caspase-1 through canonical inflammasome signaling, which leads to the release of proinflammatory cytokines IL-1beta/IL-18 and a potentially damaging inflammatory response. However, little is known about the role of caspase-1 in the liver after oxidative stress. This is especially true for the hepatocyte, a cell type that expresses and can activate the inflammasome but produces low levels of IL-1beta and IL-18. Paradoxically, during hemorrhagic shock with resuscitation (HS/R) in an in vivo mouse model associated with severe hepatic redox stress, caspase-1 activation is protective against liver injury independent of IL-1beta and IL-18. We also demonstrate that caspase-1 activation protects against cell death after redox stress in hepatocytes induced by hypoxia/reoxygenation in an in vitro model of HS/R. Mechanistically, we show that caspase-1 activation leads to reduced mitochondrial respiration and reactive oxygen species (ROS) production by increasing mitochondrial autophagy and subsequent clearance of mitochondria in hepatocytes after hypoxia/reoxygenation. During redox stress, caspase-1 increases autophagic flux through upregulation of the autophagy initiator, beclin1.;Although others have shown that ROS generated by damaged mitochondria activate the NACHT, LRR and PYD domains-containing protein 3(NLRP3) inflammasome, caspase-1 activation in the liver after oxidative stress was independent of NLRP3. We show that while the NLRP1 inflammasome is responsible for caspase-1 activation in immune cells that leads to IL-18 release after HS/R, the protective effect of caspase-1 in hepatocytes is due to the formation of an AIM2-initiated inflammasome. Our in vitro results also suggest that AIM2 is essential for the upregulation of beclin1 and mitochondrial clearance during redox stress in hepatocytes. High-mobility group box 1 (HMGB1) is a universal sentinel for nucleic acid-mediated innate immune responses. We found that HMGB1 associates with AIM2 and it is required for caspase-1 activation in hepatocytes after redox stress.;Our findings suggest a novel role for the AIM2 inflammasome and caspase-1 in regulating cellular responses to oxidative stress. We provide an important advancement in our understanding of how AIM2 and caspase-1 activation is linked with mitochondrial function and stress-induced autophagy as protective mechanisms in cells where IL1beta/IL18 are not highly expressed.