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
Open accessAbstract
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.
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Upon stimulation, CD205+ macrophages produce excessive IL-12, activating NKT cells to highly express FasL, which binds Fas upregulated on hepatocytes, triggering massive hepatocyte apoptosis and severe liver injury.
“Upon stimulation, they produce excessive IL-12, activating NKT cells to highly express FasL. This binds to Fas upregulated on hepatocytes, triggering massive hepatocyte apoptosis and severe liver injury (52).”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [52]
The Discussion (page unavailable) describes CpG-stimulated Kupffer cells releasing IL-12, which increases NKT-cell FasL expression and hepatocyte damage through FasL/Fas interaction in HBsAg-transgenic mice. The Results (page unavailable) support hepatocyte cytotoxicity and liver injury, but do not establish the claim’s stronger description of massive hepatocyte apoptosis. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn HBsAg-transgenic mice, CD205+ macrophages are hypersensitive to bacterial products from the gut (e.g., CpG ODN).
“In hepatitis B surface antigen (HBsAg)-transgenic mice, CD205+ macrophages are hypersensitive to bacterial products from the gut (e.g., CpG oligodeoxynucleotide (CpG ODN)).”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [52]
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- Authors
- Hou, X., Hao, X., Zheng, M., Xu, C., Wang, J., Zhou, R., & Tian, Z.
- Affiliations
- Anhui Medical University (CN)
- University of Science and Technology of China (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Corresponding author
- Tian, Zhigang
- Venue
- Cellular & Molecular Immunology
- Published
- 2016-04-04
- Volume
- 14
- Issue
- 8
- Pages
- 675-684
- ISSN
- 1672-7681 (ISSN-L)
- 2042-0226
- PMC
- PMC5549602
- OpenAlex
- W2338172918
- Cited by
- 41
- References
- 41
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 5 · 2020: 5 · 2019: 4 · 2018: 3 · 2017: 5
- FWCI
- 3.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cellular and Molecular Immunology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81361120388, #31390433, 91429303, 81571540)
- Topics
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- CD205, TLR9, IL-12, NKT cells, Kupffer cells, CpG oligodeoxynucleotides, liver injury, Fas ligand, Fas signaling, chronic hepatitis B, hepatocyte cytotoxicity
- MeSH terms
- Animals, Antigens, Viral, Cell Communication, Cytotoxicity, Immunologic, Hepatitis B virus, Humans, Kupffer Cells, Lymphocyte Activation, Mice, Inbred C57BL, Mice, Transgenic, Oligodeoxyribonucleotides, Receptors, Cell Surface, Signal Transduction, Antigens, CD, Minor Histocompatibility Antigens, Interleukin-12, fas Receptor, Hepatocytes, RNA, Small Interfering, Lectins, C-Type, Toll-Like Receptor 9, Mice, Fas Ligand Protein, Natural Killer T-Cells, Chemical and Drug Induced Liver Injury
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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