Journal
JOURNAL OF VIROLOGY
Volume 88, Issue 11, Pages 6128-6136Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.00333-14
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Funding
- Career Development Award from the Medical Research Council [G0800311]
- National Heart and Lung Institute Foundation [1048073]
- Wellcome Trust [087805/Z/08/Z]
- Wellcome Trust [087805/Z/08/Z] Funding Source: Wellcome Trust
- MRC [G0800311] Funding Source: UKRI
- Asthma UK [MRC-AsthmaUKCentre] Funding Source: researchfish
- Medical Research Council [G0800311, G1000758] Funding Source: researchfish
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Type I interferons (IFNs) are produced early upon virus infection and signal through the alpha/beta interferon (IFNAR1 alpha/beta)) receptor (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 displayed increased lung viral load and weight loss during RSV infection. As expected, expression of IFN-inducible genes was markedly reduced in the lungs of IFNAR1(-/)-mice. Surprisingly, we found that the levels of proinflammatory cytokines and chemokines 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-alpha was sufficient to potentiate the production 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 characterized by enhanced inflammatory cytokine production.
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