Th2 and Th17 inflammatory pathways are reciprocally regulated in asthma

摘要

Increasing evidence suggests that asthma is a heterogeneous disorder regulated\udby distinct molecular mechanisms. Here, in a cross-sectional study of asthmatics\udof varying severity (n=51), endobronchial tissue gene expression analysis\udrevealed three major patient clusters: Th2-high, Th17-high, and Th2/Th17-low.\udTh2-high and Th17-high patterns were mutually exclusive in individual patient\udsamples, and their gene signatures were inversely correlated and differentially\udregulated by IL-13 and IL-17A. To understand this dichotomous pattern of Th2\udand Th17 signatures, we investigated the potential of type 2 cytokine\udsuppression in promoting Th17 responses in a preclinical model of allergen\udinduced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased Th17\udcells and neutrophilic inflammation in the lung. However, neutralization of IL-1\udand IL-17 protected subjects from eosinophilia, mucus hyperplasia, airway\udhyperreactivity and abolished the neutrophilic inflammation, suggesting that\udcombination therapies targeting both pathways may maximize therapeutic\udefficacy across a patient population comprising both Th2 and Th17 endotypes.