DOCK2 Promotes Asthma Development by Eliciting Airway Epithelial-Mesenchymal Transition.

Epithelial-mesenchymal transition (EMT) contributes to airway remodeling, a predominant feature of asthma. Dedicator of cytokinesis 2 (DOCK2) is an innate immune signaling molecule involved in vascular remodeling. However, it is unknown if DOCK2 plays a role in airway remodeling during asthma development. In this study, we found that DOCK2 is highly induced in both normal human bronchial epithelial cells (NHBECs) treated with house dust mite (HDM) extract and human asthmatic airway epithelium. DOCK2 is also upregulated by transforming growth factor β1 (TGF-β1) during EMT of HBECs. Importantly, knockdown of DOCK2 inhibits while overexpression of DOCK2 promotes TGF-β1-induced EMT. Consistently, DOCK2 deficiency suppresses the EMT of airway epithelium, attenuates the subepithelial fibrosis, and improves pulmonary function in HDM-induced asthmatic lungs. These data suggest that DOCK2 plays an important role in EMT and asthma development. Mechanistically, DOCK2 interacts with transcription factor forkhead box M1 (FoxM1), which enhances FoxM1 binding to mesenchymal marker gene promoters and further promotes mesenchymal marker gene transcription and expression, leading to EMT. Taken together, our study identifies DOCK2 as a novel regulator for airway EMT in HDM-induced asthma model, thus providing a potential therapeutic target for treatment of asthma.