Figure 2.

The role of hepatic macrophages in viral hepatitis and hepatocellular carcinoma (HCC). (A) Hepatic macrophages and hepatitis B virus (HBV)/hepatitis C virus (HCV). Interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β produced by Kupffer cells (KCs) show strong antiviral activities. Additionally, KCs may remove infected hepatocytes by producing cytotoxic molecules, including granzyme B, perforin, reactive oxygen species, TNF-related apoptosis-inducing ligand, and Fas-ligand. KCs produce distinct chemokines, including CC- chemokine ligand (CCL)2, CCL3, CXC-chemokine ligand (CXCL)8, and CXCL9, and, together, these chemokines recruit natural killer cells, natural killer T cells, dendritic cells, and CD4+ T cells to infected sites and enhance infection clearance. HCV stimulation induces hepatic macrophages to generate CCL5, which in turn activates hepatic stellate cells and eventually triggers live inflammation and fibrosis. KCs mediate T-cell dysfunction via PD-1/PD-L1 and TIM-3/galectin-9 pathways. Increased HBV inoculum suppresses polarization of pro-inflammation macrophages. (B) Hepatic macrophages contribute to HCC. Hepatic macrophages produce IL-6, IL-1β, TNF, vascular endothelial growth factor, and platelet-derived growth factor to promote tumor growth and angiogenesis during HCC. KCs suppress antitumor activity by inducing T-cell dysfunction through PD-L1/PD-1 and galectin-9/TIM-3 in the HCC setting. In contrast, hepatic macrophages assist CD4+ T cells in removing the premalignant senescent hepatocytes that enhance HCC progression. Ly6C^hi monocytes increase the expression of S100A8 and S100A9 on cancer cells and promote tumor migration and invasion.