Th2 and Th17 inflammatory pathways are reciprocally regulated in asthma

Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. Here, 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/Th17-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 IL-13 and IL-17A. To understand this dichotomous pattern of 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-1 and IL-17 protected subjects from eosinophilia, mucus hyperplasia, 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.