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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.

Author information

1
Division of Pulmonary and Critical Care Medicine, Fibrosis Research Center and Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Medicine, University of Montreal Hospital Research Centre (CRCHUM), Montreal, Québec, Canada.
3
Division of Rheumatology, Jewish General Hospital, McGill University, Montreal, Québec, Canada.
4
The Arthritis Program, University Health Network, Toronto, Ontario, Canada.
5
Facultad de Ciencias, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico.
6
Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City, Mexico.
7
Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
8
Departments of Surgery and of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

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.

PMID:
29058717
PMCID:
PMC5720906
DOI:
10.1038/nm.4419
[Indexed for MEDLINE]
Free PMC Article

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