Alpha/beta interferon receptor signaling amplifies early proinflammatory cytokine production in the lung during respiratory syncytial virus infection

Type I interferons (IFNs) are produced early upon virus infection and signal through the alpha/beta interferon (IFN-/) recep-tor (IFNAR) to induce genes that encode proteins important for limiting viral replication and directing immune responses. To investigate the extent to which type I IFNs play a role in the local regulation of inflammation in the airways, we examined their importance in early lung responses to infection with respiratory syncytial virus (RSV). IFNAR1-deficient (IFNAR1/) mice dis-played increased lung viral load and weight loss during RSV infection. As expected, expression of IFN-inducible genes was mark-edly reduced in the lungs of IFNAR1/mice. Surprisingly, we found that the levels of proinflammatory cytokines and chemo-kines in the lungs of RSV-infected mice were also greatly reduced in the absence of IFNAR signaling. Furthermore, low levels of proinflammatory cytokines were also detected in the lungs of IFNAR1/mice challenged with noninfectious innate immune stimuli such as selected Toll-like receptor (TLR) agonists. Finally, recombinant IFN-was sufficient to potentiate the produc-tion of inflammatory mediators in the lungs of wild-type mice challenged with innate immune stimuli. Thus, in addition to its well-known role in antiviral resistance, type I IFN receptor signaling acts as a central driver of early proinflammatory responses in the lung. Inhibiting the effects of type I IFNs may therefore be useful in dampening inflammation in lung diseases character-ized by enhanced inflammatory cytokine production. IMPORTANC