Abstract
Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) is a ubiquitously expressed membrane-bound enzyme that mediates shedding of a wide variety of important regulators in inflammation including cytokines and adhesion molecules. Hepatic expression of numerous cytokines and adhesion molecules are increased in cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), however, the pathophysiological role of ADAM17 in regulating these conditions remains unknown. Therefore, we evaluated the role of ADAM17 in a mouse model of cholestatic liver injury due to bile duct ligation (BDL). We found that BDL enhanced hepatic ADAM17 protein expression, paralleled by increased ADAM17 bioactivity. Moreover, inhibition of ADAM17 bioactivity with the specific inhibitor DPC 333 significantly improved both biochemical and histological evidence of liver damage in BDL mice. Patients with cholestatic liver disease commonly experience adverse behavioral symptoms, termed sickness behaviors. Similarly, BDL in mice induces reproducible sickness behavior development, driven by the upregulated expression of cytokines and adhesion molecules that are in turn regulated by ADAM17 activity. Indeed, inhibition of ADAM17 activity significantly ameliorated BDL-associated sickness behavior development. In translational studies, we evaluated changes in ADAM17 protein expression in liver biopsies obtained from patients with PBC and PSC, compared to normal control livers. PSC and PBC patients demonstrated increased hepatic ADAM17 expression in hepatocytes, cholangiocytes and in association with liver-infiltrating immune cells compared to normal controls. In summary, cholestatic liver injury in mice and humans is associated with increased hepatic ADAM17 expression. Furthermore, inhibition of ADAM17 activity improves both cholestatic liver injury and associated sickness behavior development, suggesting that ADAM17 inhibition may represent a novel therapeutic approach for treating patients with PBC/PSC.
Highlights
Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) is type 1 transmembrane metalloprotease with wide tissue expression in the body, that facilitates the cleavage and release of a variety of substrates involved in both the initiation and propagation of inflammation [1]
The role of ADAM17 in regulating inflammation relates to its ability to process various substrates, including proinflammatory cytokines (e.g. TNFa), cytokine receptors (e.g. TNFRI/TNFRII, IL-6Ra), adhesion molecules (L-selectin, VCAM-1, ICAM-1) and growth factors (e.g. epidermal growth factor receptor (EGFR) ligands) [2,3,4, 40]
Increased tissue ADAM17 expression has been reported in different immune-mediated inflammatory diseases, including rheumatoid arthritis, psoriasis and inflammatory bowel disease highlighting its role in mediating downstream injury/inflammation [6,7,8]
Summary
Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) is type 1 transmembrane metalloprotease with wide tissue expression in the body, that facilitates the cleavage and release of a variety of substrates involved in both the initiation and propagation of inflammation [1]. In the context of inflammation, ADAM17 cleaves and releases the cytokines IL6 (and IL-6 receptor), tumor necrosis factor (TNF) a, and various adhesion molecules including ICAM-1 and VCAM-1, which critically regulate the development of numerous disease processes including sepsis, inflammatory bowel disease, psoriasis and multiple sclerosis [5,6,7,8,9,10,11,12]. This broad role played by ADAM17 in the initiation and propagation of inflammation has made the development of ADAM17 inhibitors an appealing target for treating numerous chronic inflammatory and autoimmune conditions. A number of ADAM17 inhibitors are in various stages of development for potential clinical use [1, 2, 13]
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