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Activation of NLRP3 and AIM2 inflammasomes in Kupffer cells in hepatic ischemia/reperfusion

Author:
Kim, Hyo‐Yeon, Kim, Seok‐Joo, Lee, Sun‐Mee
Source:
The FEBS journal 2015 v.282 no.2 pp. 259-270
ISSN:
1742-464X
Subject:
Kupffer cells, acetylcysteine, antibodies, antioxidants, blood serum, caspase-1, cathepsin B, gadolinium, inflammation, interleukin-1beta, ischemia, melanoma, oxidative stress, protein synthesis, protein-protein interactions, reactive oxygen species, signal transduction
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. STRUCTURED DIGITAL ABSTRACT: Panx1 physically interacts with Casp1 and asc by anti bait coip (View interaction) asc physically interacts with Aim2 by anti bait coip (View interaction)
Agid:
1379185