NLRP3 inflammasome driven liver injury and fibrosis: role of IL- 17 and TNF-alpha.

ALEXANDER WREE; MATTHEW D. MCGEOUGH; MARIA EUGENIA INZAUGARAT; CARLA A. PEÑA; ALEJANDRA CHERÑAVSKY; HAL M HOFFMAN; ARIEL E FELDSTEIN

Boston

Congreso; 65th American Association Study of Liver Diseases Annual Meeting,; 2014

AASLD

Background: The NLRP3 inflammasome, a caspase-1 activation platform critical for the processing of key pro-inflammatory cytokines has been implicated in the development acute and chronic liver diseases. However, the source and mechanisms of inflammasome mediated liver damage remains poorly understood. Therefore, our AIM was to test the hypothesis that chronic NLRP3 inflammasome activation is a central mechanism for innate immune activation and the progression of liver disease. Methods: Nlrp3D301NneoR knock-in mice on a C57BL/6 background were crossed to C57BL/6.Cg-Tg(Cre/Esr1)?Estrogen Receptor Cre (CreT) mice to induce temporal in vivo expression of mutant NLRP3 in adult mice through administration of tamoxifen. After 16 weeks of inflammasome activation, mice were sacrificed and liver tissue and serum were harvested. To dissect cell specific effects of inflammasome activation, primary hepatic cells? hepatocytes, macrophages, and hepatic stellate cells (HSC) ? were isolated from Nlrp3D301NneoR CreT mice and activation of the NLRP3 inflammasome was induced in vitro in cultured cells via 4OH-tamoxifen treatment. Results: Activation of the Nlrp3 inflammasome in Nlrp3KI CreT over 16 weeks resulted in hepatomegaly while tamoxifen-injected control mice showed regular liver weights (liver to body weight % - 6.1% ± 0.32% vs. 4.6% ± 0.03%, p < 0.05). Analysis of liver histology revealed increased inflammation with neutrophilic infiltration and increased mRNA levels of myeloperoxidase (fold-change to WT 52.8 ± 13.75, p