During viral infections, cells produce type I interferons (IFNs), which are detected by the IFNα/β receptor (IFNAR). To survive in hosts, viruses have strategies to downregulate IFN-mediated signaling. We hypothesized that macrophages, which are among the first myeloid cells to respond to viral infections, would produce a different cytokine profile if responding to ligation of pattern recognition receptors (PRRs) while IFNAR-mediated signaling was compromised. Specifically, IFNAR-mediated regulation of interleukin (IL)-1α, IL-6, IL-12, and tumor necrosis factor-α was studied in cultured murine bone marrow-derived macrophages. Since viruses like vesicular stomatitis virus can ligate PRRs such as Toll-like receptor (TLR)4 and 7, macrophages were stimulated with the TLR4 and TLR7 agonists lipopolysaccharide (LPS) or imiquimod, respectively, with or without antibody-mediated IFNAR-blockade. Cytokines and viability were assessed for 3 days poststimulation. Blocking IFNARs acutely exacerbated cytokine production by macrophages and aided their survival when they were treated with LPS. In contrast, cytokine concentrations were unaffected or slightly reduced by IFNAR blockade, but macrophages died at a greater rate when imiquimod was the stimulus. This demonstrated a differential role of IFNAR signaling in regulating PRR-induced cytokines. This suggests potential mechanisms whereby macrophages responding to viruses that inhibit type I IFN responses might contribute to excessive inflammation in some cases and inappropriately low-magnitude responses in others. This also provides a well-defined cell-based model for further dissecting the role of type I IFN signaling in macrophages responding to viral and other infections.
Keywords: Toll-like receptor; cytokines; macrophages; type I interferon receptor; virus.