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

Research output: Contribution to journalArticlepeer-review

279 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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