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Kupffer cells regulate liver recovery through induction of chemokine receptor CXCR2 on hepatocytes after acetaminophen overdose in mice

  • Organ Toxicity and Mechanisms
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Abstract

Acetaminophen (APAP) is a widely used analgesic, but also a main cause of acute liver injury in the United States and many western countries. APAP hepatotoxicity is associated with a sterile inflammatory response as shown by the infiltration of neutrophils and monocytes. While the contribution of the immune cells to promote liver repair have been demonstrated, the direct interactions between macrophages or neutrophils with hepatocytes to help facilitate hepatocyte proliferation and tissue repair remain unclear. The purpose of this study was to investigate the relationship between resident macrophages (Kupffer cells) and hepatocytes with a focus on the chemokine receptor CXCR2. C57BL/6J mice were subjected to an APAP overdose (300 mg/kg) and the role of CXCR2 on hepatocytes was investigated using a selective antagonist, SB225002. In addition, clodronate liposomes were used to deplete Kupffer cells to assess changes in CXCR2 expression. Our data showed that CXCR2 was mainly expressed on hepatocytes and it was induced specifically in hepatocytes around the necrotic area 24 h after APAP treatment. Targeting this receptor using an inhibitor caused a delayed liver recovery. Depletion of Kupffer cells significantly prevented CXCR2 induction on hepatocytes. In vitro and in vivo experiments also demonstrated that Kupffer cells regulate CXCR2 expression and pro-regenerative gene expression in surviving hepatocytes through production of IL-10. Thus, Kupffer cells support the transition of hepatocytes around the area of necrosis to a proliferative state through CXCR2 expression.

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Acknowledgements

We acknowledge the Flow Cytometry Core Laboratory, which is sponsored, in part, by the NIH/NIGMS COBRE grant P30 GM103326

Funding

This work was funded in part by a grant from National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01 DK102142 and DK125465, and National Institute of General Medicine (NIGMS) funded Liver Disease COBRE grants P20 GM103549 and P30 GM118247.

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  1. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas, KS, 66160, USA

    Nga T. Nguyen, David S. Umbaugh, Giselle Sanchez-Guerrero, Anup Ramachandran & Hartmut Jaeschke

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  1. Nga T. Nguyen
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  2. David S. Umbaugh
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Correspondence to Hartmut Jaeschke.

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Nguyen, N.T., Umbaugh, D.S., Sanchez-Guerrero, G. et al. Kupffer cells regulate liver recovery through induction of chemokine receptor CXCR2 on hepatocytes after acetaminophen overdose in mice. Arch Toxicol 96, 305–320 (2022). https://doi.org/10.1007/s00204-021-03183-0

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