Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, The University of Michigan-Ann Arbor, Ann Arbor, Michigan.
Am J Physiol Cell Physiol. 2022 Jul 1;323(1):C133-C144. doi: 10.1152/ajpcell.00067.2022. Epub 2022 May 18.
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.
特发性肺纤维化（IPF）是最常见的慢性间质性肺疾病，其特征是肺进行性瘢痕形成。转化生长因子-β（TGF-β）信号在 IPF 中起着至关重要的作用，并驱动成纤维细胞向肌成纤维细胞转化（FMT）。细胞分裂蛋白 2（DOCK2）已知通过激活 Rac 调节多种免疫功能，并最近被牵连到胸膜纤维化中。我们现在报告了 DOCK2 通过介导 FMT 在肺纤维化发展中的新作用。在原代正常和 IPF 人肺成纤维细胞（HLFs）中，TGF-β诱导 DOCK2 表达与 FMT 标志物同时发生，包括平滑肌α-肌动蛋白（α-SMA）、胶原蛋白-1 和纤维连接蛋白。DOCK2 的敲低显著减弱了 TGF-β诱导的这些 FMT 标志物的表达。此外，我们发现 TGF-β 上调 DOCK2 既依赖于 Smad3 又依赖于 ERK 途径，因为它们各自的抑制剂阻断了 TGF-β介导的诱导。TGF-β 还稳定了 DOCK2 蛋白，这有助于增加 DOCK2 的表达。此外，在 IPF 患者的肺和博来霉素中，DOCK2 也被显著诱导，TGF-β在 C57BL/6 小鼠中诱导肺纤维化。此外，在博来霉素诱导的肺纤维化模型中，增加的肺 DOCK2 表达与 FMT 标志物 α-SMA 共定位，表明 DOCK2 参与调节肺成纤维细胞表型变化。重要的是，DOCK2 缺失也减弱了博来霉素诱导的肺纤维化和 α-SMA 表达。总之，我们的研究表明 DOCK2 通过调节 FMT 在肺纤维化中发挥新作用，并表明靶向 DOCK2 可能为预防或治疗 IPF 提供一种潜在的治疗策略。
