Alfonso Tan-Garcia1,a, Lu-En Wai2,a, Dahai Zheng3, Erica Ceccarello3,4, Juandy Jo2, Nasirah Banu1, Atefeh Khakpoor1, Adeline Chia1, Christine Y. L. Tham1, Anthony T. Tan1, Michelle Hong1, Choong Tat Keng3, Laura Rivino1, Kai Chah Tan5, Kang Hoe Lee5, Norman Pavelka6, Jinmiao Chen6, Florent Ginhoux1,6, Qingfeng Chen3,7,b, Antonio Bertoletti1,2,6,b, Charles-Antoine Dutertre1,6,b
1 Program in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
2 Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Brenner Centre for Molecular Medicine, 30 Medical Drive, Singapore 117609, Singapore
3 Humanised Mouse Unit, Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Singapore 138673, Singapore
4 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive, Singapore 117545, Singapore
5 Asian American Liver Centre, Gleneagles Hospital, 6A Napier Road, Singapore 258500, Singapore
6 Singapore Immunology Network, A*STAR, 8A Biomedical Grove, Immunos Building, Level 4, Singapore 138648, Singapore
a These first authors contributed equally to this work.
b Senior authors on this work.
Published in Journal of Hepatology on 5 May 2017.
Background & aims
Liver inflammation is central to 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.
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.
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 also showed heightened pro-inflammatory responses only 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.
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.
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.
Accumulation of CD14+CD206+ myeloid cells in the liver is abrogated by reduction of intestinal microbiota perturbation in a humanised mouse model of viral-induced liver
inflammation. (A) Quantification of HBcAg+ cells as a percentage of human hepatocytes (n=3-4) in humanised mice at 2, 4 and 11-18 wpi. (B) Representative contour plots showing HLA-DR and CD206 expression by CD14+ myeloid cells in healthy and pathologic human and mouse livers. (C) Left panel: Frequency of intrahepatic CD14+HLA-DRhiCD206+ myeloid cells in mock- (4 wpi: n=4; 6-16 wpi: n=10) and HBV-infected (4 wpi: n=4; 6-16 wpi: n=11) mice at 4 or 6-16 wpi. Right panel: Frequency of CD14+HLA-DRhiCD206+ myeloid cells among human CD45+ cells (%/hCD45+) in matched livers and spleens of mock- (n=9) and HBV- (n=10) infected mice at 6-16 wpi. The Wilcoxon matched-pairs signed rank test was used for statistical analysis. (D) Quantification of serum sCD14 in mock- and HBV-infected mice with or without treatment with oral antibiotics at 6-16 wpi (n=4-7 per group). (E) Frequency of CD14+CD206+ and CD14+CD206- myeloid cells in livers of mock- (n=6-7) and HBV-infected (n=4-7) mice with or without treatment with oral antibiotics at 6-16 wpi. Data expressed as median. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.
For more information on Qinfeng CHEN's lab, please click here.