High-mobility group box 1 (HMGB1)-toll-like receptor (TLR)4-interleukin (IL)-23-IL-17A axis in drug-induced damage-associated lethal hepatitis: Interaction of γδ T cells with macrophages

Authors

  • Xuefu Wang,

    1. Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China
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  • Rui Sun,

    Corresponding author
    1. Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China
    2. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China
    • School of Life Sciences, University of Science and Technology of China, #443 Huangshan Road, Hefei 230027, China
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    • fax: 86-551-360-6783

  • Haiming Wei,

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

    Corresponding author
    1. Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China
    2. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China
    • School of Life Sciences, University of Science and Technology of China, #443 Huangshan Road, Hefei 230027, China
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    • fax: 86-551-360-6783


  • Potential conflict of interest: Nothing to report.

  • Supported by the Natural Science Foundation of China (#91029303, #30911120480, and #31021061).

Abstract

Acetaminophen overdose causes acute liver inflammation with neutrophil infiltration; however, the mechanism of damage-associated inflammation has not been elucidated. In this study we found that the HMGB1-TLR4-IL-23-IL-17A axis played a crucial role in acetaminophen-induced infiltration of neutrophils and liver injury. Notably, interleukin (IL)-17A and IL-23 significantly increased after acetaminophen challenge. A neutralizing antibody against IL-17A attenuated the recruitment of neutrophils, accompanied by reduced liver injury. Only IL-17A+CD3+γδ T cell receptor (TCR)+ cells were significantly increased in the liver, and depletion of γδ T cells, but not CD4+ T cells or natural killer (NK)T cells significantly reduced IL-17A production, attenuated liver injury, and decreased the number of neutrophils in the liver. Furthermore, a neutralizing IL-23 p19 antibody or p40-deficiency significantly decreased the levels of IL-17A and infiltration of neutrophils. After in vitro stimulation, the percentage of IL-17A-producing γδ T cells and the levels of supernatant IL-17A from total hepatic lymphocytes or purified γδ T cells markedly increased in the presence with IL-23. Importantly, IL-23 and IL-17A were reduced after inhibition of macrophages and could not be induced in Toll-like receptor TLR4−/− mice after acetaminophen challenge. Meanwhile, serum high-mobility group box 1 (HMGB1), a damage-associated molecule released from necrotic hepatocytes, increased after acetaminophen challenge, and the HMGB1 inhibitor glycyrrhizin markedly reduced the production of IL-23 and IL-17A and the recruitment of hepatic neutrophils. HMGB1 stimulated the production of IL-23 by TLR4+/+ but not by TLR4−/− macrophages. Conclusion: The HMGB1-TLR4-IL-23 pathway in macrophages makes the generation of IL-17-producing γδ T cells, which mediates neutrophil infiltration and damage-induced liver inflammation. (HEPATOLOGY 2013)

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