TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma

David F Choy, Kevin M Hart, Lee A Borthwick, Aarti Shikotra, Deepti R Nagarkar, Salman Siddiqui, Guiquan Jia, Chandra M Ohri, Emma Doran, Kevin M Vannella, Claire Butler, Beverley Hargadon, Joshua C Sciurba, Richard L Gieseck, Robert W Thompson, Sandra White, Alexander R Abbas, Janet Jackman, Lawren C Wu, Jackson G EgenLiam G Heaney, Thirumalai R Ramalingam, Joseph R Arron, Thomas A Wynn, Peter Bradding

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234 Citations (Scopus)

Abstract

Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. In a cross-sectional study of asthmatics of varying severity (n = 51), endobronchial tissue gene expression analysis revealed three major patient clusters: TH2-high, TH17-high, and TH2/17-low. TH2-high and TH17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (TH2) and TH17 signatures, we investigated the potential of type 2 cytokine suppression in promoting TH17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased TH17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both TH2 and TH17 endotypes.
Original languageEnglish
Article number301ra129
JournalScience Translational Medicine
Volume7
Issue number301
DOIs
Publication statusPublished - 19 Aug 2015

Keywords

  • Asthma
  • Heterogeneity

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  • Cite this

    Choy, D. F., Hart, K. M., Borthwick, L. A., Shikotra, A., Nagarkar, D. R., Siddiqui, S., Jia, G., Ohri, C. M., Doran, E., Vannella, K. M., Butler, C., Hargadon, B., Sciurba, J. C., Gieseck, R. L., Thompson, R. W., White, S., Abbas, A. R., Jackman, J., Wu, L. C., ... Bradding, P. (2015). TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Science Translational Medicine, 7(301), [301ra129]. https://doi.org/10.1126/scitranslmed.aab3142