Role of Kupffer cells in liver injury induced by CpG oligodeoxynucleotide and flucloxacillin in mice

Authors

  • Yuying Gao Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
  • Binbin Song Key Laboratory of Ethnomedicine (Minzu University of China), Ministry of Education, School of Pharmacy, Minzu University of China, Beijing, China
  • Shigeki Aoki Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
  • Kousei Ito Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, 260-8675, Japan, Tel: 81-43-226-2886; Fax: 81-43-226-2886; E-mail: itokousei@chiba-u.jp

DOI:

https://doi.org/10.17179/excli2020-1103

Keywords:

Kupffer cells, Toll-like receptor 9, Fas/Fas ligand, pro-inflammatory cytokines, mitochondrial permeability transition

Abstract

CpG oligodeoxynucleotide (CpG-ODN) is a Toll-like receptor 9 (TLR9) agonist that can induce innate immune responses. In a previous study, flucloxacillin (FLUX; 100 mg/kg, gavage)-induced liver injury in mice was enhanced by co-administration of CpG-ODN (40 μg/mouse, intraperitoneally). In this study, the mechanism of CpG-ODN sensitization to FLUX-induced liver injury was further investigated in mice inhibited of Kupffer cells (KCs) function by gadolinium chloride (GdCl3; 10 mg/kg, intravenously). GdCl3-treated mice administrated with CpG-ODN and FLUX showed lower liver injury than wild-type (WT) mice treated with CpG-ODN and FLUX. Upregulation of Fas and FasL by CpG-ODN was also inhibited in GdCl3-treated mice and mitochondrial swelling in response to FLUX failed to occur regardless of pre-treatment with CpG-ODN. When FasL-mutant gld/gld mice were treated with CpG-ODN, mitochondrial swelling in response to FLUX was also inhibited. These results suggest that KCs play an essential role in liver injury induced by CpG-ODN and FLUX. CpG-ODN may activate KCs, resulting in induction of Fas/FasL-mediated apoptosis of hepatocytes. The Fas/FasL pathway may also be an upstream regulator of CpG-ODN- and FLUX-induced changes in mitochondrial permeability transition. These results enhance our understanding of the mechanism of the adjuvant effect of CpG-ODN in this mouse model of liver injury.

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Published

2020-03-13

How to Cite

Gao, Y., Song, B., Aoki, S., & Ito, K. (2020). Role of Kupffer cells in liver injury induced by CpG oligodeoxynucleotide and flucloxacillin in mice. EXCLI Journal, 19, 387–399. https://doi.org/10.17179/excli2020-1103

Issue

Vol. 19 (2020)

Section

Original articles

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