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

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 antiviral 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 CD1(+) 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 TNF alpha and GM-CSF. These cells only showed heightened proinflammatory 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 proinflammatory 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. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.