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Defining critical roles for NF‐κB p65 and type I interferon in innate immunity to rhinovirus

Nathan W. Bartlett, Louise Slater, Nicholas Glanville, Jennifer J. Haas, Gaetano Caramori, Paolo Casolari, Deborah L. Clarke, Simon D. Message, Julia Aniscenko, Tatiana Kebadze, Jie Zhu, Patrick Mallia, Joseph P. Mizgerd, Maria Belvisi, Alberto Papi, Sergei V. Kotenko, Sebastian L. Johnston, Michael R. Edwards

Author Affiliations

  1. Nathan W. Bartlett1,2,3,
  2. Louise Slater1,2,3,
  3. Nicholas Glanville1,2,3,
  4. Jennifer J. Haas1,2,3,
  5. Gaetano Caramori4,
  6. Paolo Casolari4,
  7. Deborah L. Clarke3,5,
  8. Simon D. Message1,2,3,6,
  9. Julia Aniscenko1,2,3,
  10. Tatiana Kebadze1,2,3,
  11. Jie Zhu1,2,3,
  12. Patrick Mallia1,2,3,6,
  13. Joseph P. Mizgerd7,
  14. Maria Belvisi3,5,
  15. Alberto Papi4,
  16. Sergei V. Kotenko8,
  17. Sebastian L. Johnston1,2,3,6 and
  18. Michael R. Edwards (michael.edwards{at}imperial.ac.uk) *,1,2,3
  1. 1Department of Respiratory Medicine, National Heart Lung Institute, Imperial College London, London, UK
  2. 2MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
  3. 3Centre for Respiratory Infections, Imperial College London, London, UK
  4. 4Sezione di Malattie dell'Apparato Respiratorio, Centro per lo Studio delle Malattie Infiammatorie Croniche delle Vie Aeree e Patologie Fumo Correlate dell'Apparato Respiratorio (CEMICEF), University of Ferrara, Ferrara, Italy
  5. 5Respiratory Pharmacology, National Heart and Lung Institute, Imperial College London, London, UK
  6. 6Imperial College Healthcare National Health Service Trust, London, UK
  7. 7The Pulmonary Centre, Boston University School of Medicine, Boston, Massachusetts, USA
  8. 8Department of Biochemistry and Molecular Biology, University Hospital Cancer Center, UMDNJ‐New Jersey Medical School, Newark, NJ, USA
  1. *Tel: +44 0 20 7594 3775; Fax: +44 0 20 7262 8913
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Abstract

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

  • Received June 13, 2012.
  • Revision received September 19, 2012.
  • Accepted September 20, 2012.
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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.

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