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.

中文翻译：

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ADAM10介导的ephrin-B2脱落促进成肌纤维细胞活化和器官纤维化。

对慢性组织损伤的适应不良的伤口愈合反应导致器官纤维化。纤维化需要激活的成纤维细胞，导致过多的细胞外基质（ECM）沉积和组织重塑，导致适当的组织结构和器官功能丧失；然而，肌成纤维细胞活化的分子介体尚未完全确定。在这里，我们确定可溶性ephrin-B2（sEphrin-B2）作为肺和皮肤纤维化中新的proprobrotic介质。我们提供分子，功能和翻译的证据，肺损伤后膜结合的ephrin-B2的胞外域从成纤维细胞脱落进入肺泡空域。sEphrin-B2的脱落通过EphB3和/或EphB4受体信号传导促进成纤维细胞趋化性和活化。我们发现成纤维细胞中缺乏ephrin-B2的小鼠受到保护，免受皮肤和肺纤维化的影响，而整联蛋白和金属蛋白酶10（ADAM10）是成纤维细胞中主要的ephrin-B2脱落酶。ADAM10表达通过转化生长因子（TGF）-β1来增加，而TGF-β1诱导的成肌纤维细胞活化需要ADAM10介导的sEphrin-B2生成。对ADAM10的药理抑制作用可降低支气管肺泡灌洗液中sEphrin-B2的水平，并预防小鼠的肺纤维化。与小鼠数据一致，ADAM10-sEphrin-B2信号在患有特发性肺纤维化的人类受试者的成纤维细胞中被上调。这些结果揭示了组织纤维发生的新分子机制，并将sEphrin-B2，其受体EphB3和EphB4和ADAM10鉴定为治疗纤维化疾病的潜在治疗靶标。