DOCK2 contributes to pulmonary fibrosis by promoting lung fibroblast to myofibroblast transition

Idiopathic pulmonary fibrosis (IPF) is the most common chronic interstitial lung disease and is characterized by progressive scarring of the lung. Transforming growth factor-beta (TGF-beta) signaling plays an essential role in IPF and drives fibroblast to myofibroblast transition (FMT). Dedicator of cytokinesis 2 (DOCK2) is known to regulate diverse immune functions by activating Rac and has been recently implicated in pleural fibrosis. We now report a novel role of DOCK2 in pulmonary fibrosis development by mediating FMT. In primary normal and IPF human lung fibroblasts (HLFs), TGF-beta induced DOCK2 expression concurrent with FMT markers, smooth muscle a-actin (a-SMA), collagen-1, and fibronectin. Knockdown of DOCK2 significantly attenuated TGF-beta-induced expression of these FMT markers. In addition, we found that the upregulation of DOCK2 by TGF-beta is dependent on both Smad3 and ERK pathways as their respective inhibitors blocked TGF-beta-mediated induction. TGF-beta also stabilized DOCK2 protein, which contributes to increased DOCK2 expression. In addition, DOCK2 was also dramatically induced in the lungs of patients with IPF and in bleomycin, and TGF-beta induced pulmonary fibrosis in C57BL/6 mice. Furthermore, increased lung DOCK2 expression colocalized with the FMT marker alpha-SMA in the bleomycin-induced pulmonary fibrosis model, implicating DOCK2 in the regulation of lung fibroblast phenotypic changes. Importantly, DOCK2 deficiency also attenuated bleomycin-induced pulmonary fibrosis and alpha-SMA expression. Taken together, our study demonstrates a novel role of DOCK2 in pulmonary fibrosis by modulating FMT and suggests that targeting DOCK2 may present a potential therapeutic strategy for the prevention or treatment of IPF.

Automated summary

DOCK2 plays a crucial role in pulmonary fibrosis by modulating FMT, with its upregulation dependent on TGF-beta induction and Smad3, ERK pathways, and contributing to the changes in lung fibroblast phenotypes.