Introduction Non-alcoholic fatty liver disease (NAFLD) is the leading liver disease in Europe and North America. 30% of patients with NAFLD are estimated to develop inflammatory non-alcoholic steatohepatitis (NASH) with the potential to lead to cirrhosis and hepatocellular carcinoma. Current evidence suggests that gut bacterial products can drive hepatic inflammation by activating specific innate pattern recognition receptors (PRRs) such as TLR4 and the NALP3 inflammasome. Both receptors are expressed by liver resident macrophages, Kupffer cells (KCs).
Methods To determine the role of KCs and interactions with PRRs in NASH, mice were fed a methionine choline deficient (MCD) diet for three weeks to induce NASH. Liposomal clodronate was used to deplete KCs. Serum ALT levels were measured and hepatic inflammatory infiltrates characterised by flow cytometry. Real-time qPCR was used to assess changes in gene expression. Murine findings were correlated with human liver tissue from NASH patients. Groups were compared by one-way ANOVA and significance set at P < 0.05.
Results NALP3 KO (knock-out), TLR4 KO or KC deficient WT mice on a MCD diet developed reduced liver damage and decreased T lymphocyte recruitment compared to WT MCD controls. Combined KC depletion and NLRP3 KO however lead to significantly worse liver injury and progressive fibrosis as measured by collagen expression. Further investigation revealed an as yet unrecognised role for KC expressed NALP6 activation which mediated anti-inflammatory responses and modulation of hepatic IL-22 responsiveness to reduce liver injury.
KC activation through NALP3 and TLR4 increases hepatic inflammation in the MCD model of NASH.
KCs have a dual role in NASH as they also express NALP6 with anti-inflammatory properties and are able to reduce hepatic injury through modulation of IL-22 responsiveness modulation.
Disclosure of Interest None Declared
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