THE CONTRIBUTION OF CD14+ MYELOID CELLS AND GM-CSF TO VIRAL-RELATED CHRONIC LIVER INFLAMMATION

Abstract

Liver inflammation is central to the progression of chronic viral hepatitis to cirrhosis and hepatocellular carcinoma. Although CD14+ myeloid cells are recognised as key mediators of liver inflammation, a detailed functional characterisation of intrahepatic myeloid cells and their relation to chronic viral-related liver inflammation in humans is still lacking. To better define these mechanisms, detailed phenotypic, molecular and functional characterisation of intrahepatic CD14+ myeloid cells from healthy donors and patients with viral-related liver cirrhosis was performed. Unsupervised analysis revealed that chronic viral-related liver inflammation was associated with the expansion of activated myeloid cells within the liver, primarily pro-inflammatory, endotoxin non-tolerisable CD14+HLA-DRhiCD206+ cells, which spontaneously produced TNFα and GM-CSF. In HBV-infected humanised mice, a similar accumulation of CD14+HLA-DRhiCD206+ cells was detected in a temporal and liver-specific manner which was abrogated with oral antibiotic treatment. In vitro, bacterial products (LPS) increased the expression of CD206 and pro-inflammatory cytokine secretion by CD14+ myeloid cells in a GM-CSF-dependent manner, suggesting a previously undefined role for GM-CSF in chronic liver inflammation. Deciphering the interdependence of pro-inflammatory CD14+HLA-DRhiCD206+ myeloid cells, translocated bacterial products and GM-CSF now paves the way for the development of novel targeted therapeutic strategies for the treatment of patients with chronic viral hepatitis.