Premium
Airway epithelial NF ‐κB activation promotes the ability to overcome inhalational antigen tolerance
Author(s) -
Ather J. L.,
Foley K. L.,
Suratt B. T.,
Boyson J. E.,
Poynter M. E.
Publication year - 2015
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/cea.12491
Subject(s) - ovalbumin , immunology , bronchoalveolar lavage , sensitization , transgene , cytokine , in vivo , medicine , genetically modified mouse , antigen , biology , lung , biochemistry , gene , microbiology and biotechnology
Summary Background Inhalational antigen tolerance typically protects against the development of allergic airway disease but may be overcome to induce allergic sensitization preceding the development of asthma. Objectives We examined in vivo whether pre‐existing inhalational antigen tolerance could be overcome by activation of the transcription factor NF ‐κB in conducting airway epithelial cells, and used a combination of in vivo and in vitro approaches to examine the mechanisms involved. Methods Wild‐type and transgenic mice capable of expressing constitutively active IκB kinase β ( CAIKK β) in airway epithelium were tolerized to inhaled ovalbumin. Twenty‐eight days later, the transgene was transiently expressed and mice were exposed to inhaled OVA on Day 30 in an attempt to overcome inhalational tolerance. Results Following ovalbumin challenge on days 40–42, CAIKK β mice in which the transgene had been activated exhibited characteristic features of allergic airway disease, including airway eosinophilia and methacholine hyper‐responsiveness. Increases in the CD 103 + and CD 11b HI lung dendritic cell populations were present in CAIKK β mice on Day 31. Bronchoalveolar lavage from mice expressing CAIKK β mice induced CD 4 + T cells to secrete T H 2 and T H 17 cytokines, an effect that required IL ‐4 and IL ‐1 signalling, respectively. CAIKK β mice on Dox demonstrated increased numbers of innate lymphoid type 2 cells ( ILC 2) in the lung, which also exhibited elevated mRNA expression of the T H 2‐polarizing cytokine IL ‐4. Finally, airway epithelial NF ‐ kB activation induced allergic sensitization in CAIKK β mice on Dox that required IL ‐4 and IL ‐1 signalling in vivo . Conclusions Our studies demonstrate that soluble mediators generated in response to airway epithelial NF ‐κB activation orchestrate the breaking of inhalational tolerance and allergic antigen sensitization through the effects of soluble mediators, including IL ‐1 and IL ‐4, on pulmonary dendritic cells as well as innate lymphoid and CD 4 + T cells.