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 Ginhoux; Qingfeng Chen; Antonio Bertoletti; Charles-Antoine Dutertre

doi:10.1016/j.jhep.2017.04.023

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 journal › Article (Academic Journal) › peer-review

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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 language	English
Pages (from-to)	490-500
Number of pages	11
Journal	Journal of Hepatology
Volume	67
Issue number	3
DOIs	https://doi.org/10.1016/j.jhep.2017.04.023
Publication status	Published - Sept 2017

Bibliographical note

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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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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., ... Dutertre, C.-A. (2017). Intrahepatic CD206+ macrophages contribute to inflammation in advanced viral-related liver disease. Journal of Hepatology, 67(3), 490-500. https://doi.org/10.1016/j.jhep.2017.04.023

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title = "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-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.",

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",

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

year = "2017",

month = sep,

doi = "10.1016/j.jhep.2017.04.023",

language = "English",

volume = "67",

pages = "490--500",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier B.V.",

number = "3",

}

Tan-Garcia, A, Wai, L-E, Zheng, D, Ceccarello, E, Jo, J, Banu, N, Khakpoor, A, Chia, A, Tham, CYL, Tan, AT, Hong, M, Keng, CT, Rivino, L, Tan, KC, Lee, KH, Lim, SG, Newell, EW, Pavelka, N, Chen, J, Ginhoux, F, Chen, Q, Bertoletti, A & Dutertre, C-A 2017, 'Intrahepatic CD206+ macrophages contribute to inflammation in advanced viral-related liver disease', Journal of Hepatology, vol. 67, no. 3, pp. 490-500. https://doi.org/10.1016/j.jhep.2017.04.023

TY - JOUR

T1 - Intrahepatic CD206+ macrophages contribute to inflammation in advanced viral-related liver disease

AU - Tan-Garcia, Alfonso

AU - Wai, Lu-En

AU - Zheng, Dahai

AU - Ceccarello, Erica

AU - Jo, Juandy

AU - Banu, Nasirah

AU - Khakpoor, Atefeh

AU - Chia, Adeline

AU - Tham, Christine Y L

AU - Tan, Anthony T

AU - Hong, Michelle

AU - Keng, Choong Tat

AU - Rivino, Laura

AU - Tan, Kai Chah

AU - Lee, Kang Hoe

AU - Lim, Seng Gee

AU - Newell, Evan W

AU - Pavelka, Norman

AU - Chen, Jinmiao

AU - Ginhoux, Florent

AU - Chen, Qingfeng

AU - Bertoletti, Antonio

AU - Dutertre, Charles-Antoine

PY - 2017/9

Y1 - 2017/9

N2 - 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.

AB - 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.

KW - Animals

KW - Anti-Bacterial Agents/therapeutic use

KW - Gastrointestinal Microbiome

KW - HLA-DR Antigens/analysis

KW - Hepatitis, Viral, Human/drug therapy

KW - Humans

KW - Lectins, C-Type/physiology

KW - Lipopolysaccharide Receptors/analysis

KW - Macrophages/immunology

KW - Mannose-Binding Lectins/physiology

KW - Mice

KW - Myeloid Cells/physiology

KW - Receptors, Cell Surface/physiology

KW - Tumor Necrosis Factor-alpha/biosynthesis

U2 - 10.1016/j.jhep.2017.04.023

DO - 10.1016/j.jhep.2017.04.023

M3 - Article (Academic Journal)

C2 - 28483682

SN - 0168-8278

VL - 67

SP - 490

EP - 500

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 3

ER -

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

Abstract

Bibliographical note

UN SDGs

Keywords

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