Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Division of Critical Care Medicine, Department of Internal Medicine, Chung-Ang University Hospital, Seoul, South Korea.
Front Immunol. 2020 Feb 7;11:68. doi: 10.3389/fimmu.2020.00068. eCollection 2020.
Uncontrolled activation of transforming growth factor (TGF)-β results in a wide range of pathologic conditions. Therapeutic interventions to regulate TGF-β signaling during fibrosis have been developed but the effectiveness is still limited. Here, we show that developmental endothelial locus-1 (Del-1) ameliorates fibrosis in mice by inhibiting α integrin-mediated activation of TGF-β. Del-1 bound to αβ integrin, an important activator of TGF-β, and inhibited the binding of αβ integrin to the latency-associated peptide (LAP), thereby suppressing α integrin-mediated activation of TGF-β. Lack of Del-1 increased colocalization of α integrin and LAP in the lungs, which was reversed by Del-1 supplementation. The crucial role of Del-1 in regulating TGF-β activity was recapitulated in a mouse model of fibrosis using an adenovirus expressing inactive TGF-β1. Del-1 supplementation improved the pathological characteristics of the mice and reduced mortality. Thus, we propose that Del-1 is a negative regulator of TGF-β activation and a potential anti-fibrotic factor.
转化生长因子 (TGF)-β 的不受控制的激活会导致广泛的病理状况。已经开发出了用于在纤维化过程中调节 TGF-β 信号的治疗干预措施，但效果仍然有限。在这里，我们表明发育内皮定位-1 (Del-1) 通过抑制 α 整联蛋白介导的 TGF-β 激活来改善小鼠的纤维化。Del-1 与 αβ 整联蛋白结合，αβ 整联蛋白是 TGF-β 的重要激活剂，抑制了 αβ 整联蛋白与潜伏相关肽 (LAP) 的结合，从而抑制了 α 整联蛋白介导的 TGF-β 激活。缺乏 Del-1 会增加肺中 α 整联蛋白和 LAP 的共定位，而 Del-1 的补充则可以逆转这种情况。在使用表达无活性 TGF-β1 的腺病毒的纤维化小鼠模型中，Del-1 可重复调节 TGF-β 活性的关键作用。Del-1 的补充改善了小鼠的病理特征并降低了死亡率。因此，我们提出 Del-1 是 TGF-β 激活的负调节剂和潜在的抗纤维化因子。
