IRF3 inhibits inflammatory signaling pathways in macrophages to prevent viral pathogenesis.

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 mice. mice, upon respiratory virus infection, showed increased susceptibility and mortality. deficiency caused enhanced inflammatory gene expression, lung inflammation, immunopathology, and damage, accompanied by increased infiltration of pro-inflammatory macrophages. Deletion of in macrophages () displayed, similar to 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 lungs. Targeted analyses revealed activated MAPK signaling in lungs. Therefore, IRF3 inhibited inflammatory signaling pathways in macrophages to prevent viral inflammation and pathogenesis.