Extended IL-4 priming of macrophages induces an antiviral state that restricts lymphocytic choriomeningitis virus replication.

Viruses such as lymphocytic choriomeningitis virus (LCMV) and Lassa virus can directly suppress macrophage (Mϕ) activation, leading to viral chronicity and severe disease. Recent studies have shown that prolonged IL-4 stimulation induces a proinflammatory M2a phenotype, which upon subsequent TLR stimulation exhibits unique immune parameters. However, the innate immune response of such M2a Mϕ to virus infections remains unknown. Here, we investigated the response of IL-4-activated spleen-derived Mϕ (SpM) to LCMV infection to understand how IL-4 induced polarization influences the Mϕ - virus interactions. We discovered that IL-4 induced Mϕ were less permissive to LCMV infection. Moreover, gene analyses revealed the polarized IL-4 stimulated Mϕ expressed more inflammatory cytokines, higher levels of antiviral genes, and antigen presentation molecules compared to unpolarized Mϕ after infection. In addition, we detected unique protein-expression profiles involving innate recognition molecules and transcription factors in the RIG-I-like receptor (RLR) pathway, which may contribute to reduced LCMV replication. In conclusion, our data suggest that M1 and prolonged IL-4 polarized Mϕ exhibit distinct molecular profiles that may be associated with the observed diminished LCMV infection.