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Infiltrating neutrophils aggravate metabolic liver failure in fah-deficient mice

Authors

  • Ziping Qi,

    1. Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
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  • Xin Wang,

    1. The Key Laboratory of National Education Ministry for Mammalian Reproductive Biology and Biotechnology, Inner Mongolia University, Huhhot, China
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  • Haiming Wei,

    1. Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
    2. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
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  • Rui Sun,

    1. Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
    2. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
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  • Zhigang Tian

    Corresponding author
    1. Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
    2. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
    • Correspondence

      Zhigang Tian, School of Life Sciences,

      University of Science & Technology of China,

      443 Huang-Shan Road, Hefei, 230027, China

      Tel: 86 551 6360 0845

      Fax: 86 551 6360 6783

      e-mail: tzg@ustc.edu.cn

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Abstract

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 (DAMPs) 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 CCR2 chemokine, with neutrophils expressing more CCR2. CCR2 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 CCR2.

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