CD205-TLR9-IL-12 axis contributes to CpG-induced oversensitive liver injury in HBsAg transgenic mice by promoting the interaction of NKT cells with Kupffer cells

Cell Mol Immunol. 2017 Aug;14(8):675-684. doi: 10.1038/cmi.2015.111. Epub 2016 Apr 4.


Gut-derived bacterial products contribute to liver inflammation and injury during chronic hepatitis B virus infection; however, the underlying mechanisms remain obscure. In this study, hepatitis B surface antigen transgenic (HBs-Tg) mice and their wild-type (WT) control C57BL/6 mice were injected with CpG-oligodeoxynucleotides (ODNs) to mimic the translocation of gut microbial products into the systemic circulation. We found that, compared with the WT mice, the HBs-Tg mice were oversensitive to CpG-ODN-induced liver injury, which was dependent on natural killer T (NKT) cells. CpG-ODN injection enhanced the expression of Fas ligand (FasL) on NKT cells. In addition, hepatocytes from the HBs-Tg mice expressed higher levels of Fas than did those from the WT mice, which was further augmented by CpG-ODN. Interaction of Fas and FasL was involved in the cytotoxicity of NKT cells against hepatocytes in the HBs-Tg mice. Moreover, Kupffer cells in the HBs-Tg mice expressed higher levels of CD205 and produced greater amounts of interleukin (IL)-12 than did those in the WT mice. Finally, the depletion of Kupffer cells, neutralization of IL-12 or specific silencing of CD205 on Kupffer cells significantly inhibited CpG-ODN-induced liver injury and NKT activation in the HBs-Tg mice. Our data suggest that CD205-expressing Kupffer cells respond to CpG-ODNs and subsequently release IL-12 to promote NKT cell activation. Activated NKT cells induce liver damage through the Fas signaling pathway in HBs-Tg mice.

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Antigens, Viral / genetics
  • Cell Communication
  • Chemical and Drug Induced Liver Injury / immunology*
  • Cytotoxicity, Immunologic
  • Fas Ligand Protein / metabolism
  • Hepatitis B virus / physiology*
  • Hepatocytes / physiology*
  • Humans
  • Interleukin-12 / metabolism
  • Kupffer Cells / immunology*
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Minor Histocompatibility Antigens / genetics
  • Minor Histocompatibility Antigens / metabolism*
  • Natural Killer T-Cells / immunology*
  • Oligodeoxyribonucleotides / administration & dosage
  • RNA, Small Interfering / genetics
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction
  • Toll-Like Receptor 9 / metabolism*
  • fas Receptor / metabolism


  • Antigens, CD
  • Antigens, Viral
  • CPG-oligonucleotide
  • DEC-205 receptor
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Lectins, C-Type
  • Minor Histocompatibility Antigens
  • Oligodeoxyribonucleotides
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • fas Receptor
  • Interleukin-12