Aim The current study explored the therapeutic value of IL-1R1
blockade in hepatocytes in two models of NAFLD-associated hepatocarcinogenesis.
Methods 1) DEN was used starting at 2 weeks of age in male
hepatocyte-specific IL-1R1-deficient (KO) mice and WT littermates. From 6 weeks of
age mice were fed a high-fat, high-carbohydrate diet (HFD) or a corresponding
control diet (CD) up until 24 weeks of age. 2) Low-dose weekly CCl4 in combination
with a high-fat, high-fructose, high-cholesterol western diet (WD) or CD was given
to 8-week-old, male KO and WT mice for 12 weeks.
Results All DEN-treated mice fed a HFD developed an obese phenotype
and macrovesicular hepatic steatosis with mildly elevated ALT, however IL-1R1
deficiency improved insulin resistance and prevented injurious hepatic JNK
activation from DEN+HFD. Additionally, the number of macroscopically visible
tumor nodules in KO mice was reduced by 43% compared to WT littermates with
a significant reduction of tumor nodules>1mm. This translated in a
significant reduction of tumor load in the KO. Only WT mice showed an infiltration
of CD8+T cells and MDSCs from DEN+HFD. In the CCl4 model, the
addition of a WD did not produce the same extent of metabolic derangement and liver
histology and ALT levels were comparable between both genotypes. As seen with the
DEN+HFD model, WT mice developed a higher number of dysplastic
nodules>1mm compared to the KO (62.5% vs. 28.6%).
Conclusion The inhibition of IL-1R1 signaling specifically in
hepatocytes could be an adjunctive concept to current immunomodulation in NAFLD-HCC
treatment.
