The role of liver macrophages in viral liver pathogenesis

Abstract

Liver macrophages play important roles in the pathophysiology of liver fibrosis and hepatocellular carcinoma. However, liver macrophages are a heterogenous population and have differing roles in maintenance of liver function and response in disease. In a healthy liver, macrophages play a critical role in antigen processing, maintaining tolerance to the high levels of gut-derived bacterial products, and regulating inflammation through cytokine response. However, macrophages also play a critical role in liver pathology, specifically in the context of viral infection. The liver is targeted by multiple viruses, including human immunodeficiency virus, hepatitis B virus, and hepatitis C virus, which dysregulate macrophage functions to affect liver disease. Infection with any of these viruses is associated with increased risk of developing hepatocellular carcinoma, and coinfection further accelerates the progression to liver disease and cancer. However, the exact mechanisms by which liver macrophages contribute to disease in the context of viral infections are not well defined. This is a particularly acute issue in human immunodeficiency virus-infected populations, which have high incidence of hepatitis B virus and hepatitis C virus coinfection. To address this knowledge gap, this review describes the populations of macrophages in the liver, outlines the current models and limitations associated with the study of liver macrophages, discusses the function and role of liver macrophages in the context of viral infection, and describes the mechanisms by which these cells contribute to hepatocellular carcinoma and fibrosis. We then use this information to propose focus areas for the liver macrophage field to better address and resolve viral liver disease.

Keywords: HBV; HCC; HCV; HIV; macrophage.

Fig. 1.

Model of effects of viral proteins and infection on LMs. Coinfection is represented on the left and monoinfection on the right. Effects of HBV proteins on LMs are represented in yellow, HIV in red, and HCV in blue. Effects of LMs on cells are represented in green boxes. Proposed interactions in coinfection are represented with a dotted line. Created in BioRender. Gaskill, P. (2025) https://BioRender.com/m8p32su.