title: 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.
abstract: 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.
authors.affiliation: Anhui Provincial Laboratory of Microbiology and Parasitology, Department of Microbiology and Parasitology, Anhui Medical University, Hefei 230032, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Hou
authors.affiliation: Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Hao
authors.affiliation: Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Innovation Center for Cell Biology, Hefei National Laboratory for Physical Sciences at Microscale, Hefei 230027, China.
authors.forename: Congfei
authors.initials: C
authors.lastname: Xu
authors.affiliation: Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.|Innovation Center for Cell Biology, Hefei National Laboratory for Physical Sciences at Microscale, Hefei 230027, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.|Innovation Center for Cell Biology, Hefei National Laboratory for Physical Sciences at Microscale, Hefei 230027, China.
authors.forename: Rongbin
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.|Innovation Center for Cell Biology, Hefei National Laboratory for Physical Sciences at Microscale, Hefei 230027, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000956:Antigens, Viral / Q000235:genetics; D002450:Cell Communication; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein / Q000378:metabolism; D006515:Hepatitis B virus / Q000502:physiology*; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D007728:Kupffer Cells / Q000276:immunology*; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D055611:Natural Killer T-Cells / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000956:Antigens, Viral; C408982:CPG-oligonucleotide; C093569:DEC-205 receptor; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D009838:Oligodeoxyribonucleotides; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D019014:fas Receptor; D018664:Interleukin-12