title: Caspase 1 activation is protective against hepatocyte cell death by up-regulating beclin 1 protein and mitochondrial autophagy in the setting of redox stress.
abstract: Caspase 1 activation can be induced by oxidative stress, which leads to the release of the proinflammatory cytokines IL1β and IL18 in myeloid cells and a potentially damaging inflammatory response. However, little is known about the role of caspase 1 in non-immune cells, such as hepatocytes, that express and activate the inflammasome but do not produce a significant amount of IL1β/IL18. Here we demonstrate that caspase 1 activation protects against cell death after redox stress induced by hypoxia/reoxygenation in hepatocytes. Mechanistically, we show that caspase 1 reduces mitochondrial respiration and reactive oxygen species by increasing mitochondrial autophagy and subsequent clearance of mitochondria in hepatocytes after hypoxia/reoxygenation. Caspase 1 increases autophagic flux through up-regulating autophagy initiator beclin 1 during redox stress and is an important cell survival factor in hepatocytes. We find that during hemorrhagic shock with resuscitation, an in vivo mouse model associated with severe hepatic redox stress, caspase 1 activation is also protective against liver injury and excessive oxidative stress through the up-regulation of beclin 1. Our findings suggest an alternative role for caspase 1 activation in promoting adaptive responses to oxidative stress and, more specifically, in limiting reactive oxygen species production and damage in cells and tissues where IL1β/IL18 are not highly expressed.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Sun
authors.forename: Wentao
authors.initials: W
authors.lastname: Gao
authors.forename: Patricia
authors.initials: P
authors.lastname: Loughran
authors.forename: Rick
authors.initials: R
authors.lastname: Shapiro
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Scott
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D001343:Autophagy; D000071186:Beclin-1; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010101:Oxygen Consumption / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D020382:Interleukin-18; D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; D020170:Caspase 1
keywords: Autophagy; Cell Death; Hemorrhagic Shock; Liver Injury; Mitochondria; Mitochondrial Autophagy; Reactive Oxygen Species (ROS)