Research ArticleAsthma

TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma

Science Translational Medicine  19 Aug 2015:
Vol. 7, Issue 301, pp. 301ra129
DOI: 10.1126/scitranslmed.aab3142

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A tale of two asthmas

Classifying diseases according to symptoms is rapidly becoming a thing of the past. Targeted therapeutics have shown us that sets of symptoms can be caused by different pathogenic mechanisms. Now, Choy et al. demonstrate that asthma can be divided into three immunological clusters: TH2-high, TH17-high, and TH2/17-low. The TH2-high and TH17-high clusters were inversely correlated in patients. Moreover, neutralizing one signature promoted the other in a mouse model of asthma. These data suggest that combination therapies targeting both pathways may better treat asthmatic individuals.

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.

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