ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis.
ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis.
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DOI：
10.1038/nm.4419
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发表时间：
2017-12
期刊：
影响因子：
82.9
通讯作者：
Kapoor M
中科院分区：
文献类型：
--
作者：
Lagares D;Ghassemi-Kakroodi P;Tremblay C;Santos A;Probst CK;Franklin A;Santos DM;Grasberger P;Ahluwalia N;Montesi SB;Shea BS;Black KE;Knipe R;Blati M;Baron M;Wu B;Fahmi H;Gandhi R;Pardo A;Selman M;Wu J;Pelletier JP;Martel-Pelletier J;Tager AM;Kapoor M
慢性组织损伤的不适应伤口愈合反应导致器官纤维化。纤维化包括过度的细胞外基质（ECM）沉积和活化的肌成纤维细胞的组织重塑，导致正常组织结构和器官功能的丧失；然而，肌成纤维细胞活化的分子介质尚未完全确定。在这里，我们发现可溶性ephrin-B2在肺和皮肤纤维化中是一种新的促纤维化介质。我们提供了分子，功能和翻译证据，证明膜结合的ephrin-B2在肺损伤后从成纤维细胞脱落到肺泡空域。可溶性ephrin-B2 （sEphrin-B2）的脱落通过EphB3/EphB4受体信号传导促进成纤维细胞趋化和活化。我们发现，在成纤维细胞中缺乏ephrin-B2的小鼠免受皮肤和肺纤维化的保护，并且在成纤维细胞中分离整合素和金属蛋白酶10 （ADAM10）是主要的ephrin-B2脱落酶。ADAM10是由转化生长因子-β1 （TGF-β1）诱导的，而TGF-β1诱导的肌成纤维细胞活化需要ADAM10介导的sEphrin-B2生成。药理抑制ADAM10可降低小鼠支气管肺泡灌洗液中sEphrin-B2水平，防止肺纤维化。与小鼠数据一致，ADAM10/sEphrin-B2信号在特发性肺纤维化患者的成纤维细胞中上调。这些结果揭示了组织纤维化发生的新的分子机制，并确定了sEphrin-B2及其受体Eph3/Eph4和ADAM10是治疗纤维化疾病的潜在靶点。
Maladaptive wound healing responses to chronic tissue injury result in organ fibrosis. Fibrosis, which entails excessive extracellular matrix (ECM) deposition and tissue remodelling by activated myofibroblasts, leads to loss of proper tissue architecture and organ function; however the molecular mediators of myofibroblast activation remain to be fully identified. Here we identify soluble ephrin-B2 as a novel pro-fibrotic 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 soluble ephrin-B2 (sEphrin-B2) promotes fibroblast chemotaxis and activation via EphB3/EphB4 receptor signaling. We found that mice lacking ephrin-B2 in fibroblasts are protected from skin and lung fibrosis and that a distintegrin and metalloproteinase 10 (ADAM10) is the major ephrin-B2 sheddase in fibroblasts. ADAM10 is induced by transforming growth factor-β1 (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 Eph3/Eph4, and ADAM10 as potential therapeutic targets in the treatment of fibrotic diseases.
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影响因子：
64.8
作者：
Himanen, JP;Rajashankar, KR;Nikolov, DB
通讯作者：
Nikolov, DB
影响因子：
16
作者：
Gerety, SS;Wang, HU;Anderson, DJ
通讯作者：
Anderson, DJ
影响因子：
3.3
作者：
Le Gall, Sylvain M.;Bobe, Pierre;Blobel, Carl P.
通讯作者：
Blobel, Carl P.
影响因子：
--
作者：
Lagares, David;Busnadiego, Oscar;Garcia-Fernandez, Rosa Ana;Kapoor, Mohit;Liu, Shangxi;Carter, David E.;Abraham, David;Shi-Wen, Xu;Carreira, Patricia;Fontaine, Benjamin A.;Shea, Barry S.;Tager, Andrew M.;Leask, Andrew;Lamas, Santiago;Rodriguez-Pascual, Fernando
通讯作者：
Rodriguez-Pascual, Fernando
DOI：
10.2174/1386207053258488
发表时间：
2005-03-01
影响因子：
1.8
作者：
Ludwig, A;Hundhausen, C;Becherer, JD
通讯作者：
Becherer, JD