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

May 18, 2022American journal of physiology. Cell physiology

DOCK2 may promote lung scarring by helping lung support cells change into scar-forming cells

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Abstract

Increased lung DOCK2 expression is associated with pulmonary fibrosis in patients and mouse models.

Transforming growth factor-β (TGF-β) induces DOCK2 expression in both normal and idiopathic pulmonary fibrosis (IPF) human lung fibroblasts.
DOCK2 expression coincides with markers of fibroblast to myofibroblast transition (FMT), such as smooth muscle α-actin, collagen-1, and fibronectin.
Knockdown of DOCK2 reduces TGF-β-induced expression of FMT markers.
The upregulation of DOCK2 by TGF-β is dependent on Smad3 and ERK signaling pathways.
DOCK2 is notably induced in the lungs of IPF patients and in mouse models of pulmonary fibrosis.
DOCK2 deficiency mitigates bleomycin-induced pulmonary fibrosis and α-SMA expression.

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Idiopathic pulmonary fibrosis (IPF) is the most common chronic interstitial lung disease and is characterized by progressive scarring of the lung. Transforming growth factor-β (TGF-β) 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-β induced DOCK2 expression concurrent with FMT markers, smooth muscle α-actin (α-SMA), collagen-1, and fibronectin. Knockdown of DOCK2 significantly attenuated TGF-β-induced expression of these FMT markers. In addition, we found that the upregulation of DOCK2 by TGF-β is dependent on both Smad3 and ERK pathways as their respective inhibitors blocked TGF-β-mediated induction. TGF-β 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-β induced pulmonary fibrosis in C57BL/6 mice. Furthermore, increased lung DOCK2 expression colocalized with the FMT marker α-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 α-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.

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

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