title: Activation of NLRP3 and AIM2 inflammasomes in Kupffer cells in hepatic ischemia/reperfusion.
abstract: Inflammasome activation by danger signals in ischemia/reperfusion (I/R) injury is responsible for the sterile inflammatory response. Signals triggering formation and activation of the inflammasome involve the generation of oxidative stress. The aim of this study was to examine the molecular mechanisms of inflammasome activation and the involvement of reactive oxygen species in hepatic I/R. I/R induced the formation of nucleotide-binding domain leucine-rich repeat containing family pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasomes and the subsequent serum release of interleukin 1β. Pannexin-1 inhibitor and anti-cathepsin B antibody attenuated I/R-induced inflammasome activation and hepatic injury. The expression of the thioredoxin-interacting protein gene and the interaction between NLRP3 and the thioredoxin-interacting protein increased after I/R. Treatment with the antioxidant N-acetylcysteine significantly attenuated protein conversion of interleukin 1β after hepatic I/R. Moreover, pannexin-1 protein expression and cathepsin B release were strongly attenuated by N-acetylcysteine. The depletion of Kupffer cells with gadolinium chloride markedly decreased NLRP3 and AIM2 inflammasome expression and activation of their signaling pathways, and also reduced the level of caspase-1 protein in F4/80-positive cells. Our findings suggest that reactive-oxygen-species-mediated activation of NLRP3 and AIM2 inflammasomes leads to I/R-induced inflammatory responses in which Kupffer cells play a crucial role.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: Hyo-Yeon
authors.initials: HY
authors.lastname: Kim
authors.forename: Seok-Joo
authors.initials: SJ
authors.lastname: Kim
authors.forename: Sun-Mee
authors.initials: SM
authors.lastname: Lee
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis*; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000276:immunology; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D006801:Humans; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000097:blood; D007728:Kupffer Cells / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018384:Oxidative Stress / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology
chemical_list: C540422:Aim2 protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D002401:Cathepsin B; D000111:Acetylcysteine
keywords: inflammasome; interleukin-1β; ischemia/reperfusion; liver; reactive oxygen species