Intrahepatic CD206+ macrophages contribute to inflammation in advanced viral-related liver disease
Abstract
Background & aims Liver inflammation is key in the progression of chronic viral hepatitis to cirrhosis and hepatocellular carcinoma. The magnitude of viral replication and the specific anti-viral immune responses should govern the degree of inflammation, but a direct correlation is not consistently found in chronic viral hepatitis patients. We aim to better define the mechanisms that contribute to chronic liver inflammation. Methods Intrahepatic CD14+ myeloid cells from healthy donors (n=19) and patients with viral-related liver cirrhosis (HBV, HBV/HDV or HCV; n=15) were subjected to detailed phenotypic, molecular and functional characterisation. Results Unsupervised analysis of multi-parametric data showed that liver disease was associated with the intrahepatic expansion of activated myeloid cells mainly composed of pro-inflammatory CD14+HLA-DR hi CD206+ cells, which spontaneously produced TNFα and GM-CSF. These cells only showed heightened pro-inflammatory responses to bacterial TLR agonists and were more refractory to endotoxin-induced tolerance. A liver-specific enrichment of CD14+HLA-DR hi CD206+ cells was also detected in a humanised mouse model of liver inflammation. This accumulation was abrogated following oral antibiotic treatment, suggesting a direct involvement of translocated gut-derived microbial products in liver injury. Conclusions Viral-related chronic liver inflammation is driven by the interplay between non-endotoxin-tolerant pro-inflammatory CD14+HLA-DR hi CD206+ myeloid cells and translocated bacterial products. Deciphering this mechanism paves the way for the development of therapeutic strategies specifically targeting CD206+ myeloid cells in viral-related liver disease patients. Lay summary: Viral-related chronic liver disease is driven by intrahepatic pro-inflammatory myeloid cells accumulating in a gut-derived bacterial product-dependent manner. Our findings support the use of oral antibiotics to ameliorate liver inflammation in these patients.
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In patients with virus-related (HBV/HCV) cirrhosis, an expanded intrahepatic CD14+HLA-DRhiCD206+ macrophage subset with defective endotoxin tolerance is found.
“Another study in patients with virus-related (HBV/Hepatitis C virus (HCV)) cirrhosis found an expanded intrahepatic CD14+HLA-DRhiCD206+ macrophage subset with defective endotoxin tolerance.”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [54]
Upon persistent exposure to gut microbial products, CD14+HLA-DRhiCD206+ macrophages continuously secrete TNF-α and GM-CSF, driving chronic liver inflammation.
“Upon persistent exposure to gut microbial products, instead of downregulating inflammation, they continuously secrete TNF-α and GM-CSF, driving chronic liver inflammation (54).”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [54]
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- Authors
- Tan-Garcia, A., Wai, L.-E., Zheng, D., Ceccarello, E., Jo, J., Banu, N., Khakpoor, A., Chia, A., Tham, C. Y. L., Tan, A. T., Hong, M., Keng, C. T., Rivino, L., Tan, K. C., Lee, K. H., Lim, S. G., Newell, E. W., Pavelka, N., Chen, J., Ginhoux, F., Chen, Q., Bertoletti, A., & Dutertre, C.-A.
- Affiliations
- Duke-NUS Medical School (SG)
- Agency for Science, Technology and Research (SG)
- Gleneagles Hospital (SG)
- National University of Singapore (SG)
- Corresponding author
- Dutertre, Charles-Antoine
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 67
- Issue
- 3
- Pages
- 490-500
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W2610177544
- Cited by
- 68
- References
- 54
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 8 · 2023: 7 · 2022: 9 · 2021: 11 · 2020: 10 · 2019: 6 · 2018: 8 · 2017: 1
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion)
- Funders
- National Medical Research Council (NMRC/BNIG/2026/2014, NMRC/STaR/013/2012)
- Agency for Science, Technology and Research (A 619/STAR, NMRC/TCR/014-NUHS/2015)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- CD206+ macrophages, chronic viral hepatitis, liver cirrhosis, liver inflammation, HLA-DR, endotoxin tolerance, oral antibiotics, TNF-α, GM-CSF, humanized mice, hepatitis B, hepatitis C, hepatitis D
- MeSH terms
- Gastrointestinal Microbiome, Mannose Receptor, Animals, Anti-Bacterial Agents, Hepatitis, Viral, Human, HLA-DR Antigens, Humans, Macrophages, Receptors, Cell Surface, Tumor Necrosis Factor-alpha, Lipopolysaccharide Receptors, Myeloid Cells, Lectins, C-Type, Mannose-Binding Lectins, Mice
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