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Nat Med. 2017 Dec;23(12):1405-1415. doi: 10.1038/nm.4419. Epub 2017 Oct 23.
ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis.
Lagares D1, Ghassemi-Kakroodi P2, Tremblay C2, Santos A1, Probst CK1, Franklin A1, Santos DM1, Grasberger P1, Ahluwalia N1, Montesi SB1, Shea BS1, Black KE1, Knipe R1, Blati M2, Baron M3, Wu B4, Fahmi H2, Gandhi R4, Pardo A5, Selman M6, Wu J2, Pelletier JP2, Martel-Pelletier J2, Tager AM1, Kapoor M2,4,7,8.
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.