Intrahepatic CD206+ macrophages contribute to inflammation in advanced viral-related liver disease

Alfonso Tan-Garcia, Lu-En Wai, Dahai Zheng, Erica Ceccarello, Juandy Jo, Nasirah Banu, Atefeh Khakpoor, Adeline Chia, Christine Y L Tham, Anthony T Tan, Michelle Hong, Choong Tat Keng, Laura Rivino, Kai Chah Tan, Kang Hoe Lee, Seng Gee Lim, Evan W Newell, Norman Pavelka, Jinmiao Chen, Florent GinhouxQingfeng Chen, Antonio Bertoletti, Charles-Antoine Dutertre

Research output: Contribution to journalArticle (Academic Journal)peer-review

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-DRhiCD206+ 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-DRhiCD206+ 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-DRhiCD206+ 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.

Original languageEnglish
Pages (from-to)490-500
Number of pages11
JournalJournal of Hepatology
Volume67
Issue number3
DOIs
Publication statusPublished - Sep 2017

Bibliographical note

Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Keywords

  • Animals
  • Anti-Bacterial Agents/therapeutic use
  • Gastrointestinal Microbiome
  • HLA-DR Antigens/analysis
  • Hepatitis, Viral, Human/drug therapy
  • Humans
  • Lectins, C-Type/physiology
  • Lipopolysaccharide Receptors/analysis
  • Macrophages/immunology
  • Mannose-Binding Lectins/physiology
  • Mice
  • Myeloid Cells/physiology
  • Receptors, Cell Surface/physiology
  • Tumor Necrosis Factor-alpha/biosynthesis

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