Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States.
Am J Physiol Lung Cell Mol Physiol. 2023 Sep 1;325(3):L342-L351. doi: 10.1152/ajplung.00066.2023. Epub 2023 Jul 25.
Progressive pulmonary fibrosis is a devastating condition and current treatment is suboptimal. There has been considerable interest in the role of tyrosine kinase signaling as mediators of pro- and antifibrotic processes. Nintedanib is a nonspecific tyrosine kinase that has been shown to have therapeutic benefit in lung fibrosis. However, the precise mechanism of action remains unclear because nintedanib inhibits several tyrosine kinases, which are often expressed on multiple cell types with different activities during fibrosis. Discoidin domain receptor 2 (DDR2) has been suggested as a potential target of nintedanib. DDR2 is a receptor tyrosine kinase that is activated by fibrillar collagens such as type I collagen. DDR2 is primarily expressed by fibroblasts. The effectiveness of specifically targeting DDR2 signaling during fibrosis remains undefined. In the present study, we show that nintedanib acts as a direct and indirect inhibitor of DDR2. We then utilize a novel allosteric inhibitor of DDR2, WRG-28, which blocks ligand binding and activation of DDR2. We find that WRG-28 augments fibroblast apoptosis and attenuates fibrosis. Finally, we show that fibroblast type I collagen autocrine signaling is regulated by DDR2 through both kinase-dependent and kinase-independent functions of DDR2. These findings highlight the importance of type I collagen autocrine signaling by fibroblasts during fibrosis and demonstrate that DDR2 has a central role in this pathway making it a potential therapeutic target. Type I collagen is a major component of fibrosis and can signal through cell surface receptors such as discoidin domain receptor 2 (DDR2). DDR2 activation can lead to further collagen deposition by fibroblasts setting up a profibrotic positive feedback loop. In this report, we find that inhibition of DDR2 with nintedanib or a specific DDR2 inhibitor, WRG-28, can disrupt this cycle and prevent fibrosis through augmented fibroblast apoptosis and inhibited activation.
进行性肺纤维化是一种破坏性疾病，目前的治疗方法并不理想。酪氨酸激酶信号转导作为促纤维化和抗纤维化过程的介质，引起了人们的极大兴趣。尼达尼布是一种非特异性酪氨酸激酶抑制剂，已被证明对肺纤维化具有治疗益处。然而，其确切的作用机制仍不清楚，因为尼达尼布抑制了几种酪氨酸激酶，这些激酶通常在纤维化过程中在多种具有不同活性的细胞类型上表达。离散域受体 2 (DDR2) 已被认为是尼达尼布的潜在靶点。DDR2 是一种受体酪氨酸激酶，可被纤维胶原（如 I 型胶原）激活。DDR2 主要由成纤维细胞表达。在纤维化过程中特异性靶向 DDR2 信号的有效性尚未确定。在本研究中，我们表明尼达尼布可直接和间接抑制 DDR2。然后，我们利用一种新型 DDR2 别构抑制剂 WRG-28，该抑制剂可阻断 DDR2 的配体结合和激活。我们发现 WRG-28 可增强成纤维细胞凋亡并减轻纤维化。最后，我们发现成纤维细胞 I 型胶原自分泌信号通过 DDR2 的激酶依赖和非依赖功能调节。这些发现强调了纤维化过程中成纤维细胞 I 型胶原自分泌信号的重要性，并表明 DDR2 在该途径中具有核心作用，使其成为潜在的治疗靶点。I 型胶原是纤维化的主要成分，可通过细胞表面受体（如 DDR2）传递信号。DDR2 的激活可导致成纤维细胞进一步沉积胶原，从而建立起促纤维化的正反馈环。在本报告中，我们发现用尼达尼布或特定的 DDR2 抑制剂 WRG-28 抑制 DDR2 可以破坏这一循环，通过增强成纤维细胞凋亡和抑制激活来预防纤维化。
