Defining critical roles for NF-κB p65 and type I interferon in innate immunity to rhinovirus
Article first published online: 14 NOV 2012
Copyright © 2012 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 4, Issue 12, pages 1244–1260, December 2012
How to Cite
Bartlett, N. W., Slater, L., Glanville, N., Haas, J. J., Caramori, G., Casolari, P., Clarke, D. L., Message, S. D., Aniscenko, J., Kebadze, T., Zhu, J., Mallia, P., Mizgerd, J. P., Belvisi, M., Papi, A., Kotenko, S. V., Johnston, S. L. and Edwards, M. R. (2012), Defining critical roles for NF-κB p65 and type I interferon in innate immunity to rhinovirus. EMBO Mol Med, 4: 1244–1260. doi: 10.1002/emmm.201201650
- Issue published online: 4 DEC 2012
- Article first published online: 14 NOV 2012
- Manuscript Accepted: 20 SEP 2012
- Manuscript Revised: 19 SEP 2012
- Manuscript Received: 13 JUN 2012
- Funded Access
The importance of NF-κB activation and deficient anti-viral interferon induction in the pathogenesis of rhinovirus-induced asthma exacerbations is poorly understood. We provide the first in vivo evidence in man and mouse that rhinovirus infection enhanced bronchial epithelial cell NF-κB p65 nuclear expression, NF-κB p65 DNA binding in lung tissue and NF-κB-regulated airway inflammation. In vitro inhibition of NF-κB reduced rhinovirus-induced pro-inflammatory cytokines but did not affect type I/III interferon induction. Rhinovirus-infected p65-deficient mice exhibited reduced neutrophilic inflammation, yet interferon induction, antiviral responses and virus loads were unaffected, indicating that NF-κB p65 is required for pro-inflammatory responses, but redundant in interferon induction by rhinoviruses in vivo. Conversely, IFNAR1−/− mice exhibited enhanced neutrophilic inflammation with impaired antiviral immunity and increased rhinovirus replication, demonstrating that interferon signalling was critical to antiviral immunity. We thus provide new mechanistic insights into rhinovirus infection and demonstrate the therapeutic potential of targeting NF-κB p65 (to suppress inflammation but preserve anti-viral immunity) and type I IFN signalling (to enhance deficient anti-viral immunity) to treat rhinovirus-induced exacerbations of airway diseases.
See accompanying article http://dx.doi.org/10.1002/emmm.201202032