IRF3 inhibits inflammatory signaling pathways in macrophages to prevent viral pathogenesis | Science Advances

Viral inflammation contributes to pathogenesis and mortality during respiratory virus infections. IRF3, a critical component of innate antiviral immune responses, interacts with pro-inflammatory transcription factor NF-κB, and inhibits its activity. This mechanism helps suppress inflammatory gene expression in virus-infected cells and mice. We evaluated the cells responsible for IRF3-mediated suppression of viral inflammation using newly engineered conditional Irf3 ^Δ/Δ mice. Irf3 ^Δ/Δ mice, upon respiratory virus infection, showed increased susceptibility and mortality. Irf3 deficiency caused enhanced inflammatory gene expression, lung inflammation, immunopathology, and damage, accompanied by increased infiltration of pro-inflammatory macrophages. Deletion of Irf3 in macrophages ( Irf3 ^MKO ) displayed, similar to Irf3 ^Δ/Δ mice, increased inflammatory responses, macrophage infiltration, lung damage, and lethality, indicating that IRF3 in these cells suppressed lung inflammation. RNA-seq analyses revealed enhanced NF-κB–dependent gene expression along with activation of inflammatory signaling pathways in infected Irf3 ^MKO lungs. Targeted analyses revealed activated MAPK signaling in Irf3 ^MKO lungs. Therefore, IRF3 inhibited inflammatory signaling pathways in macrophages to prevent viral inflammation and pathogenesis.