Liver Macrophage Polarization and Function in Hepatotropic Viral Infection

The liver maintains an immunologically tolerant environment as a result of continuous exposure to food and bacterial constituents from the digestive tract. Hepatotropic pathogens such as hepatitis C virus (HCV) can take advantage of this niche and establish lifelong chronic infections causing hepatic fibrosis, and hepatocellular carcinoma. Macrophages (Mϕ) play a critical role in regulation of immune responses to hepatic infection and regeneration of tissue. However, the factors crucial for Mϕ in limiting hepatic inflammation or resolving liver damage have not been fully understood. In this work, we demonstrate that expression of the C-type lectin receptor scavenger receptor-AI (SR-AI) is crucial for promoting M2-like Mϕ activation and polarization during hepatic inflammation. Liver Mϕ uniquely upregulated SR-AI during hepatotropic adenoviral infection and displayed increased expression of alternative Mϕ activation markers such as YM-1, arginase-1, and IL-10 via the activation of Mertk associated with inhibition of mTOR. The expression of these molecules was reduced on Mϕ obtained from the livers of infected mice deficient for the gene encoding SR-AI (msr1). Furthermore, in vitro studies using an SR-AI-deficient Mϕ cell line revealed impeded M2 polarization and decreased phagocytic capacity. Direct stimulation with virus was sufficient to activate M2 gene expression in the wild type (WT) cell line but not in the knockdown cell line. Importantly, tissue damage and fibrosis were exacerbated in SR-AI-/- mice following hepatic infection. In contrast, adoptive transfer of WT bone marrow derived Mϕ conferred protection against fibrosis in these mice. Taken together, these findings demonstrate that SR-AI expression on liver Mϕ promotes recovery from infection-induced tissue damage by mediating a switch to a pro-resolving Mϕ polarization state.