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

Abstract

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 <i>Irf3</i>^Δ/Δ mice. <i>Irf3</i>^Δ/Δ mice, upon respiratory virus infection, showed increased susceptibility and mortality. <i>Irf3</i> deficiency caused enhanced inflammatory gene expression, lung inflammation, immunopathology, and damage, accompanied by increased infiltration of pro-inflammatory macrophages. Deletion of <i>Irf3</i> in macrophages (<i>Irf3^MKO</i>) displayed, similar to <i>Irf3</i>^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 <i>Irf3^MKO</i> lungs. Targeted analyses revealed activated MAPK signaling in <i>Irf3^MKO</i> lungs. Therefore, IRF3 inhibited inflammatory signaling pathways in macrophages to prevent viral inflammation and pathogenesis.