NLRP6 Inflammasome Modulates Disease Progression in a Chronic-Plus-Binge Mouse Model of Alcoholic Liver Disease.

Rebecca Elena Mainz,Eicke Latz,Tobias Otto,Madhuri Haque,Thomas Clavel,Kai Markus Schneider,Christian Trautwein,Roland Sonntag,Stefanie Albers,Nicole Simone Treichel

doi:10.3390/cells11020182

Rebecca Elena Mainz, Eicke Latz + Show 8 more

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https://doi.org/10.3390/cells11020182

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Abstract

A considerable percentage of the population is affected by alcoholic liver disease (ALD). It is characterized by inflammatory signals from the liver and other organs, such as the intestine. The NLR family pyrin domain containing 6 (NLRP6) inflammasome complex is one of the most important inflammatory mediators. The aim of this study was to evaluate a novel mouse model for ALD characterized by 8-week chronic-plus-binge ethanol administration and to investigate the role of NLRP6 inflammasome for intestinal homeostasis and ALD progression using Nlrp6-/- mice. We showed that chronic-plus-binge ethanol administration triggers hepatic steatosis, injury, and neutrophil infiltration. Furthermore, we discovered significant changes of intestinal microbial communities, including increased relative abundances of bacteria within the phyla Bacteroidota and Campilobacterota, as well as reduced Firmicutes. In this ALD model, inhibiting NLRP6 signaling had no effect on liver steatosis or damage, but had a minor impact on intestinal homeostasis via affecting intestinal epithelium function and gut microbiota. Surprisingly, Nlrp6 loss resulted in significantly decreased hepatic immune cell infiltration. As a result, our novel mouse model encompasses several aspects of human ALD, such as intestinal dysbiosis. Interfering with NLRP6 inflammasome activity reduced hepatic immune cell recruitment, indicating a disease-aggravating role of NLRP6 during ALD.

Highlights

Alcoholic liver disease (ALD) encompasses a spectrum of diseases ranging from simple liver steatosis and alcoholic hepatitis to liver cirrhosis and hepatocellular carcinoma
Analysis of liver enzymes in serum confirmed that chronic ethanol treatment triggered mild but consistent liver injury, as indicated by increased concentration of aspartate transaminase (AST), alanine transaminase (ALT), and glutamate dehydrogenase (GLDH) (Figure 1c)
Data represent mean ± standard error of the mean (SEM) of at least five mice per group; *** p < 0.001, ** p < 0.01, * p < 0.05, ns = not significant. These results indicate that this long-term chronic-plus-binge model recapitulates the drinking behavior of chronic alcoholism in humans, and displays most of the molecular characteristics associated with the development of ALD in these patients, including elevated liver injury, steatosis, and neutrophil infiltration

Summary

Introduction

Alcoholic liver disease (ALD) encompasses a spectrum of diseases ranging from simple liver steatosis and alcoholic hepatitis to liver cirrhosis and hepatocellular carcinoma. About 90% of individuals with excessive alcohol consumption will develop liver steatosis, which will progress to steatohepatitis and even liver cirrhosis in about 50% and 25% of cases, respectively [2]. The determinants of disease progression in ALD are incompletely understood, the innate immune system and inflammatory signals between the intestine and the liver, termed the gut-liver axis, seem to play an important role [3]. In mouse models of ALD, chronic feeding of alcohol led to intestinal bacterial overgrowth, as well as intestinal dysbiosis, characterized by changes in the taxonomic composition of the intestinal microbiota [4]. Intestinal dysbiosis, bacterial overgrowth, and enhanced translocation of bacterial components from gut to liver may in turn impact liver function. Animal models of ALD have shown that repetitive exposure to bacterial LPS triggers activation of hepatic macrophages [7]

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