解整合素金属蛋白酶10介导的肝配蛋白B2脱落促进肌纤维细胞活化和器官纤维化
文献 ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis 发表在 Nature Medicine 原文链接
Abstract：Maladaptive wound healing responses to chronic tissue injury result in organ fibrosis. Fibrosis, which entails excessive extracellular matrix (ECM) deposition and tissue remodeling by activated myofibroblasts, leads to loss of proper tissue architecture and organ function; however, the molecular mediators of myofibroblast activation have yet to be fully identified. Here we identify soluble ephrin-B2 (sEphrin-B2) as a new profibrotic mediator in lung and skin fibrosis. We provide molecular, functional and translational evidence that the ectodomain of membrane-bound ephrin-B2 is shed from fibroblasts into the alveolar airspace after lung injury. Shedding of sEphrin-B2 promotes fibroblast chemotaxis and activation via EphB3 and/or EphB4 receptor signaling. We found that mice lacking ephrin-B2 in fibroblasts are protected from skin and lung fibrosis and that a disintegrin and metalloproteinase 10 (ADAM10) is the major ephrin-B2 sheddase in fibroblasts. ADAM10 expression is increased by transforming growth factor (TGF)-β1, and ADAM10-mediated sEphrin-B2 generation is required for TGF-β1-induced myofibroblast activation. Pharmacological inhibition of ADAM10 reduces sEphrin-B2 levels in bronchoalveolar lavage and prevents lung fibrosis in mice. Consistent with the mouse data, ADAM10-sEphrin-B2 signaling is upregulated in fibroblasts from human subjects with idiopathic pulmonary fibrosis. These results uncover a new molecular mechanism of tissue fibrogenesis and identify sEphrin-B2, its receptors EphB3 and EphB4 and ADAM10 as potential therapeutic targets in the treatment of fibrotic diseases.
摘要：慢性组织损伤创面愈合的不良反应会导致器官纤维化。纤维化是指细胞外基质(ECM)过量沉积和肌成纤维细胞活化的组织重塑，导致组织结构和器官功能的丧失。然而，激活肌成纤维细胞的分子介质尚未完全确定。我们发现可溶性的肝配蛋白B2是一种新的肺和皮肤纤维化的前纤维素介质。在肺损伤后ephrin-B2的外显子结构域从成纤维细胞脱落进入肺泡空隙。sEphrin-B2的脱落促进成纤维细胞趋化与EphB 3和/或EphB 4受体信号激活。研究发现缺乏ephrin-B2的小鼠成纤维细胞不发生皮肤和肺纤维化。在成纤维细胞中，解整合素金属蛋白酶10是主要的肝配蛋白B2脱落酶。转化生长因子(TGF)-β1可以促进ADAM 10的表达，转化生长因子(TGF)-β1诱导肌成纤维细胞活化的过程需要ADAM 10介导sEfrain-B2的脱落。ADAM 10的药理作用降低小鼠支气管肺泡灌洗液中sEfrain-B2水平并预防肺纤维化。与小鼠实验数据趋势一致，ADAM 10-sEfrain-B2信号在特发性肺纤维化患者的成纤维细胞中表达升高。这些结果揭示了一种新的组织纤维化的分子机制，其受体EphB 3、EphB 4和ADAM 10可作为治疗纤维性疾病的潜在靶点。
使用试剂原文信息：sEphrin-B2 levels in human and mouse BAL fluids and in human plasma were determined by ELISA (Uscn Life Science Inc., SEE112Hu, SEE112Mu) according to the manufacturer’s protocol.