IL-17A induces signal transducers and activators of transcription-6- independent airway mucous cell metaplasia

Dawn C. Newcomb, Madison G. Boswell, Taylor P. Sherrill, Vasiliy V. Polosukhin, Kelli L. Boyd, Kasia Goleniewska, Steven L. Brody, Jay K. Kolls, Kenneth B. Adler, R. Stokes Peebles

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23 Scopus citations

Abstract

Mucous cell metaplasia is a hallmark of asthma, and may be mediated by signal transducers and activators of transcription (STAT)-6 signaling. IL-17A is increased in the bronchoalveolar lavage fluid of patients with severe asthma, and IL-17A also increases mucus production in airway epithelial cells. Asthma therapeutics are being developed that inhibit STAT6 signaling, but the role of IL-17A in inducing mucus production in the absence of STAT6 remains unknown. Wehypothesizedthat IL-17A inducesmucouscell metaplasia independent of STAT6, and we tested this hypothesis in two murine models in which increased IL-17A protein expression is evident. In the first model, ovalbumin (OVA)-specific D011.10 Th17 cells were adoptively transferred into wild-type (WT) or STAT6 knockout (KO) mice, and the mice were challenged with OVA or PBS. WT-OVA and STAT6 KO-OVA mice demonstrated increased airway IL-17A and IL- 13 protein expression and mucous cell metaplasia, compared with WT-PBS or STAT6 KO-PBS mice. In the second model, WT, STAT1 KO, STAT1/STAT6 double KO (DKO), or STAT1/STAT6/IL-17 receptor A (RA) tripleKO(TKO) mice were challenged with respiratory syncytial virus (RSV) or mock viral preparation, and the mucous cells were assessed.STAT1KO-RSVmicedemonstratedincreasedairwaymucous cell metaplasia compared with WT-RSV mice. STAT1 KO-RSV and STAT1/STAT6 DKO-RSV mice also demonstrated increased mucous cell metaplasia, compared with STAT1/STAT6/IL17RA TKO-RSV mice. We also treated primarymurine tracheal epithelial cells (mTECs) from WT and STAT6 KOmice. STAT6 KOmTECs showed increased periodic acid-Schiff staining with IL-17A but not with IL-13. Thus, asthma therapies targeting STAT6 may increase IL-17A protein expression, without preventing IL-17A-induced mucus production.

Original languageEnglish
Pages (from-to)711-716
Number of pages6
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume48
Issue number6
DOIs
StatePublished - Jun 1 2013

Keywords

  • Asthma
  • IL-13
  • IL-17A
  • Mucous cell metaplasia
  • STAT6

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    Newcomb, D. C., Boswell, M. G., Sherrill, T. P., Polosukhin, V. V., Boyd, K. L., Goleniewska, K., Brody, S. L., Kolls, J. K., Adler, K. B., & Peebles, R. S. (2013). IL-17A induces signal transducers and activators of transcription-6- independent airway mucous cell metaplasia. American Journal of Respiratory Cell and Molecular Biology, 48(6), 711-716. https://doi.org/10.1165/rcmb.2013-0017OC