NLRP3 inflammasome activation in D-galactosamine and lipopolysaccharide-induced acute liver failure: Role of heme oxygenase-1

作者：Kim Seok Joo; Lee Sun Mee^*

来源：Free Radical Biology and Medicine, 2013, 65: 997-1004.

DOI：10.1016/j.freeradbiomed.2013.08.178

• Acute liver failure
• Heme oxygenase-1
• Interleukin-1 beta
• NLRP3 inflammasome
• Reactive oxygen species
• Free radicals

D-Galactosamine (GaIN) and lipopolysaccharide (LPS) are commonly used to study mechanisms of hepatic malfunction that result in hepatic inflammation and subsequent fulminant hepatic failure. Inflammasomes are intracellular multiprotein complexes that in response to cellular danger signals trigger the biological maturation of proinflammatory cytokines. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that induces anti-inflammatory and antioxidant activity against oxidative cellular stress. This study examined activation of the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome in GaIN/LPS-induced hepatic injury and the role of HO-1 in the signaling pathways of inflammasome. Mice (C57BL/6) were pretreated twice with hemin (HO-1 inducer, 30 mg/kg) and zinc protoporphyrin (ZnPP; HO-1 inhibitor, 10 mg/kg) at 12 and 2 h before GaIN (800 mg/kg)/LPS (40 mu g/kg) administration. HO-1 induction with hemin reversed the lethality induced by GaIN/LPS administration, and ZnPP pretreatment blocked this change. Lipid peroxidation markedly increased after GaIN/LPS treatment, whereas glutathione content decreased in the GaIN/LPS group. These changes were attenuated by hemin, but ZnPP reversed the effects of hemin. Serum levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1 beta increased after GaIN/LPS treatment; these increases were attenuated by hemin. Hepatic mRNA levels of TNF-alpha, IL-1 beta, and NLRP3 increased after GaIN/LPS treatment, and hemin attenuated increases in TNF-a and IL-1 beta. After GaIN/LPS treatment, the hepatic expression of NLRP3, ASC, and caspase-1 (p10) was increased. In immunoprecipitation studies, hemin attenuated the interaction of NLRP3 with ASC and caspase-1. GaIN/LPS induced expression of the thioredoxin-interacting protein (TXNIP) gene and the interaction between NLRP3 and TXNIP; again, hemin attenuated these effects. The effects of hemin were reversed by ZnPP. Our findings suggest that activation of the NLRP3 inflammasome leads to a GaIN/LPS-induced inflammatory response through TXNIP-NLRP3 interaction. Furthermore, HO-1 overexpression may protect the liver against GaIN/LPS-induced inflammation through suppression of the NLRP3 signaling pathway.

• 出版日期2013-12