Redox‐dependent regulation of hepatocyte absent in melanoma 2 inflammasome activation in sterile liver injury in mice

Abstract

Sterile liver inflammation, such as liver ischemia reperfusion, hemorrhagic shock after trauma and drug-induced liver injury is initiated and regulated by endogenous mediators including DNA and reactive oxygen species. Here we identify a novel mechanism for redox-mediated regulation of AIM2-inflammasome activation in hepatocytes after redox stress in mice, which occurs via interaction with cytosolic HMGB1. We show that in liver during hemorrhagic shock in mice, and in hepatocytes after hypoxia with reoxygenation, cytosolic HMGB1 associates with AIM2 and is required for activation of caspase-1 in response to cytosolic DNA. Activation of caspase-1 via AIM2 leads to subsequent hepatoprotective responses such as autophagy. HMGB1 binds to AIM2 at a non-DNA-binding site on the HIN-domain of AIM2 to facilitate inflammasome and caspase-1 activation in hepatocytes. Furthermore, binding of HMGB1 to AIM2 is stronger with fully-reduced all-thiol HMGB1 than with partially oxidized disulfide-HMGB1, and binding strength corresponds to caspase-1 activation. These data suggest HMGB1 redox status regulates AIM2 inflammasome activation. Conclusion Our findings suggest a novel and important mechanism for regulation of AIM2 inflammasome activation in hepatocytes during redox stress. Our study may suggest broader implications for how this and other inflammasomes are activated and how their activation is regulated during cell stress, as well as the mechanisms of inflammasome regulation in non-immune cell types.

Inflammasome and Autophagy Regulation: A Two-way Street

“…Moreover, in vivo induction of autophagy by AIM2 inflammasome was protective by inducing removal of ROS-generating mitochondria in the liver (13,53). Similar to the previous study with RalB, beclin1 was an important mediator in autophagy activation mediated by AIM2 (13,53). In contrast, in hepatocytes, AIM2-dependent regulation of autophagy was mediated by caspase-1, suggesting that mechanisms of AIM2-mediated autophagy regulation may differ between immune and nonimmune cell types (53,54).…”

“…Another mechanism by which autophagy regulates inflammasome activation is through p62-dependent deg-has now been confirmed in two separate models (13,52). In the first model, AIM2 activation by host-derived dsDNA led to increased autophagic flux in hepatocytes after redox stress induced by hypoxia with reoxygenation (13).…”

“…Similarly, NLRP3 is activated through association with Nek7, which is able to bind in response to activation by multiple NLRP3 activators that cause a drop in intracellular potassium levels (12). Even AIM2, which has been shown to directly bind dsDNA for activation, is able to use high mobility group box 1 (HMGB1) to enhance activation and regulate its activation in response to redox stress through differences in the affinity of HMGB1 binding in different oxidized states (13). In general, however, inflammasome activation is regulated by the levels of activating stimuli, be they endogenous or exogenous, as well as the availability of individual inflammasome components, which are kept at low levels of expression in innate immune responders such as macrophages (3).…”

“…In the first model, AIM2 activation by host-derived dsDNA led to increased autophagic flux in hepatocytes after redox stress induced by hypoxia with reoxygenation (13). Moreover, in vivo induction of autophagy by AIM2 inflammasome was protective by inducing removal of ROS-generating mitochondria in the liver (13,53).…”

Effect of Hepatic Artery Spasm on a Rat Model of Hepatic Ischemia‐Reperfusion Injury

“…These results may have been due to treatment with PHT, which expanded the hepatic artery and the small branches of the artery in the liver, relieved the arterial spasm, increased liver perfusion, and improved the hepatic microcirculation. [14][15][16] The pathologic results revealed that a smaller hepatic artery diameter and a depressed vessel wall were observed at 30 minutes after reperfusion in the control group, and these results were not detected in other groups. 17 This finding also provides strong evidence of the occurrence of a hepatic artery spasm.…”