ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis

肌成纤维细胞 ADAM10型 纤维化 细胞外基质 细胞生物学 癌症研究 伤口愈合 生物 以法林 病理 成纤维细胞 免疫学 化学 去整合素 信号转导 医学 基质金属蛋白酶 金属蛋白酶 内科学 细胞培养 遗传学
作者
David Lagares,Parisa Ghassemi-Kakroodi,Caroline Tremblay,Alba Santos,Clemens K. Probst,Alicia Franklin,Daniela M. Santos,Paula Grasberger,Neil Ahluwalia,Sydney B. Montesi,Barry S. Shea,Katharine E. Black,Rachel S. Knipe,Meryem Blati,Murray Baron,Brian Wu,Hassan Fahmi,Rajiv Gandhi,Annie Pardo,Moisés Selman
出处
期刊:Nature Medicine [Nature Portfolio]
卷期号:23 (12): 1405-1415 被引量:127
标识
DOI:10.1038/nm.4419
摘要

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.
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