ISG15 Regulates Peritoneal Macrophages Functionality against Viral Infection

Abstract

Upon viral infection, the production of type I interferon (IFN) and the subsequent upregulation of IFN stimulated genes (ISGs) generate an antiviral state with an important role in the activation of innate and adaptive host immune responses. The ubiquitin-like protein (UBL) ISG15 is a critical IFN-induced antiviral molecule that protects against several viral infections, but the mechanism by which ISG15 exerts its antiviral function is not completely understood. Here, we report that ISG15 plays an important role in the regulation of macrophage responses. ISG15−/− macrophages display reduced activation, phagocytic capacity and programmed cell death activation in response to vaccinia virus (VACV) infection. Moreover, peritoneal macrophages from mice lacking ISG15 are neither able to phagocyte infected cells nor to block viral infection in co-culture experiments with VACV-infected murine embryonic fibroblast (MEFs). This phenotype is independent of cytokine production and secretion, but clearly correlates with impaired activation of the protein kinase AKT in ISG15 knock-out (KO) macrophages. Altogether, these results indicate an essential role of ISG15 in the cellular immune antiviral response and point out that a better understanding of the antiviral responses triggered by ISG15 may lead to the development of therapies against important human pathogens. Modification of proteins by ubiquitin (UB) and ubiquitin-like proteins (UBLs) are key regulatory processes of the innate and adaptive immune response. Interferon (IFN) stimulated gene product 15 (ISG15) is an ubiquitin-like protein modifier, which is reversibly conjugated to different viral and cellular proteins mediating considerable antiviral responses. In turn, many viruses, including poxviruses, have evolved strategies to block the antiviral and inflammatory effects of the innate immune responses to keep cells alive until virus replication is completed. Here, we describe a novel function of ISG15 in the control of macrophages activation, phagocytosis and apoptosis in response to viral infection. These processes are essential for the self-defense mechanism to protect animals from infectious disease and could be crucial to understand the ISG15 antiviral activity described in animal models.