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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The results of this study show that alloxan-induced diabetes altered the histone H3 acetylation pattern and compromised the chromatin supraorganization in corneal tissue/cells. Continued research is needed to understand the clinical and morphofunctional significance of changes in corneal cell nuclei of diabetic individuals.

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Our results show that KCS promotes chromatin remodeling in epithelial cells and lymphocytes on the conjunctival surface of dogs. The changes described in this study are different from those reported for conjunctival cell nuclei of human KCS patients.

Background & Aims: Chronic liver injury leads to activation of hepatic stellate cells (HSCs), which transdifferentiate into HSC myofibroblasts and produce the extracellular matrix (ECM) that forms the fibrotic scar. While the progression of fibrosis is understood to be the cause of end stage liver disease, there are currently no approved therapies directed at interfering with the activity of HSC myofibroblasts. Methods: We performed a high-throughput small interfering RNA (siRNA) screen in primary human HSC myofibroblasts targeting RNAs from >9,500 genes to identify those that promote the fibrotic phenotype of HSCs. The screen identified ABHD17B (Abhydrolase domain containing 17B, depalmitoylase), which was evaluated through loss-of -function studies in multiple primary human HSC lines. Structural analysis was performed to identify key amino acids in the hydrolase pocket of ABHD17B, and depalmitoylase inhibitors were evaluated. Protein partners were identified by mass spectrometry (MS), and Abhd17b-/- mice were challenged with carbon tetrachloride (CCl4) as a model of chronic liver injury. Results: Depletion of ABHD17B promotes the inactivation of HSCs, characterized by reduced COL1A1 and ACTA2 expression and accumulation of lipid droplets. RNA-seq and MS analysis also indicated a broader impact on ECM production and cytoskeletal organization. Mice deficient in Abhd17b are viable, demonstrate normal liver histology, and are protected from fibrosis in the setting of in vivo liver injury. While ABHD17B is a depalmitoylase, inhibiting this function alone is not sufficient to affect the fibrotic activity of HSCs. Conclusions: ABHD17B promotes fibrosis through pathways independent of depalmitoylation that include regulating expression of COL1A1 and other ECM genes and interacting with proteins involved in cytoskeletal organization, contractility, and adhesion. Targeting ABHD17B may have potential as an antifibrotic therapy.