ADAM Metalloproteinase Domain 17 Regulates Cholestasis-Associated Liver Injury and Sickness Behavior Development in Mice

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.

Association between the expression levels of ADAMTS16 and BMP2 and tumor budding in hepatocellular carcinoma

“…To the best of our knowledge, no study has reported the association of ADAMTS family members with cholestasis. However, a close relative of the ADAMTS family, ADAM17, has been reported to be related to cholestasis ( 43 ). Increased ADAM17 expression was found in patients with two important cholestatic liver diseases, including primary biliary cholangitis and primary sclerosing cholangitis ( 43 ).…”

Acute severe hepatitis as a presenting symptom in clinically stable patients admitted with SARS-CoV-2 Omicron infection

“…Immunohistochemistry was performed on the slides as described. 10 In brief, endogenous peroxidase activity was inhibited with 3% hydrogen peroxide. The slides were then blocked with 4% goat serum before being incubated with a primary mouse antibody against SARS-CoV-2 (GeneTex GTX632604, Clone1A9) overnight at 4°C.…”

The protease ADAM17 at the crossroads of disease: revisiting its significance in inflammation, cancer, and beyond

“…Mice lacking Timp3 , a specific endogenous inhibitor of ADAM17 activity, serve as a model of ADAM17 gain of function, and exhibit hepatic lymphocyte infiltration and necrosis, mainly due to constitutive ADAM17‐dependent TNFα signaling in the liver [60]. Moreover, pharmacologic inhibition of ADAM17 using the selective small molecule inhibitor DPC‐333 ameliorated liver injury in a bile duct ligation‐induced mouse model of cholestatic liver injury [61].…”