Infiltrating neutrophils aggravate metabolic liver failure in fah‐deficient mice

Background & Aims Mice deficient in tyrosine catabolic enzyme fumarylacetoacetate hydrolase ( fah − / − ) was a useful animal model for studying liver failure. Tyrosine metabolic toxicants accumulate in hepatocytes over time in fah − / − mice, leading to hepatocyte necrosis which we propose release many type of damage associated molecular patterns ( DAMP s) and cause chronic inflammation. However, whether immune‐mediated inflammations cause a second wave of liver damage in fah −/− mice have never been investigated. Methods The progressive changes in body weight, survival rate and liver inflammation were examined after the protective drug ( NTBC ) withdrawal. Cell depletion and receptor blocking were used to define the key immune cells and molecules in liver injury. Results After removing of NTBC , fah −/− mice lost their body weight gradually, and finally died when the body weight largely reduced (low to 70%), along with increased serum ALT and total bilirubin. Importantly, a large amount of liver‐infiltrating neutrophils were observed. Neutrophils depletion reduced the liver failure, and resulted in a better survival of fah −/− mice after NTBC withdrawal. The liver tissues produce more CCR 2 chemokine, with neutrophils expressing more CCR 2. CCR 2 inhibition reduced the number of liver‐infiltrating neutrophils and increased the expression of repair cytokine IL ‐22, with a longer survival of fah −/− mice after NTBC withdrawal. Conclusions The excess infiltrating neutrophils exacerbate liver failure in fah −/− mice which can be attenuated by blocking CCR 2.