Type I interferon limits influenza virus-induced acute lung injury by regulation of excessive inflammation in mice

• IFNAR KO mice exhibited increased mortality after infection with influenza A/FM/1/47.
• The level of proinflammatory cytokines increased in IFNAR KO mice after infection.
• The production of IL-10 was impaired in IFNAR KO mice after infection.
• IFNAR signaling was critical to induce IL-10 production.
• Restoration of IL-10 to IFNAR KO mice alleviated cytokine storm and improved mortality.

Antiviral immune responses play as a double edged sword in resolution of infection and pathogenesis of acute lung injury caused by infection with highly pathogenic influenza A viruses. Here we show that type I interferons (IFNs) are important in protection against acute influenza A virus infection not only via their antiviral activity but also via their anti-inflammatory activity. IFN α receptor (IFNAR) knock-out (KO) mice exhibited increased mortality and morbidity with higher viral load after infection with influenza virus A/FM/1/47 (H1N1, a mouse-adapted strain) compared with wild-type (WT) mice, though the viruses were finally eliminated in both groups. The levels of proinflammatory cytokines in the lungs were significantly higher, while the level of IL-10 in the lungs was significantly lower in IFNAR KO mice than in WT mice during the course of infection. Restoration of IL-10 during an ongoing virus infection significantly reduced the levels of proinflammatory cytokines and improved mortality of IFNAR KO mice. These results suggest that type I IFNs are responsible not only for direct resolution of viral load but also for suppression of immunopathology caused by influenza A virus through IL-10 production.