iRhom2 inhibits bile duct obstruction-induced liver fibrosis.

Abstract

Chronic liver disease can induce prolonged activation of hepatic stellate cells, which may result in liver fibrosis. Inactive rhomboid protein 2 (iRhom2) is required for the maturation of A disintegrin and metalloprotease 17 (ADAM17, also called TACE), which is responsible for the cleavage of membrane-bound tumor necrosis factor-α (TNF-α) and its receptors (TNFRs). Here, using the murine bile duct ligation (BDL) model, we showed that the abundance of iRhom2 and activation of ADAM17 increased during liver fibrosis. Consistent with this, concentrations of ADAM17 substrates were increased in plasma samples from mice after BDL and in patients suffering from liver cirrhosis. We observed increased liver fibrosis, accelerated disease progression, and an increase in activated stellate cells after BDL in mice lacking iRhom2 (Rhbdf2-/- ) compared to that in controls. In vitro primary mouse hepatic stellate cells exhibited iRhom2-dependent shedding of the ADAM17 substrates TNFR1 and TNFR2. In vivo TNFR shedding after BDL also depended on iRhom2. Treatment of Rhbdf2-/- mice with the TNF-α inhibitor etanercept reduced the presence of activated stellate cells and alleviated liver fibrosis after BDL. Together, these data suggest that iRhom2-mediated inhibition of TNFR signaling protects against liver fibrosis.

• Authors: Balamurugan Sundaram, Kristina Behnke, Andrea Belancic, Mazin A Al-Salihi, Yasser Thabet, Robin Polz, Rossella Pellegrino, Yuan Zhuang, Prashant V Shinde, Haifeng C Xu, Jelena Vasilevska, Thomas Longerich, Diran Herebian, Ertan Mayatepek, Hans H Bock, Petra May, Claus Kordes, Nima Aghaeepour, Tak W Mak, Verena Keitel, Dieter Häussinger, Jürgen Scheller, Aleksandra A Pandyra, Karl S Lang, Philipp A Lang
• Journal: Science signaling (Sci Signal) Vol. 12 Issue 605 (10 29 2019) ISSN: 1937-9145 [Electronic] United States
• PMID: 31662486 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Carrier Proteins
• Receptors, Tumor Necrosis Factor, Type I
• Receptors, Tumor Necrosis Factor, Type II
• iRhom2 protein, mouse
• ADAM17 Protein
• Etanercept

Topics

• ADAM17 Protein (genetics, metabolism)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Bile Ducts (surgery)
• Carrier Proteins (genetics, metabolism)
• Cells, Cultured
• Cholestasis (genetics, metabolism)
• Etanercept (pharmacology)
• Gene Expression Regulation
• Hepatic Stellate Cells (drug effects, metabolism)
• Humans
• Ligation
• Liver Cirrhosis (genetics, metabolism, prevention & control)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Receptors, Tumor Necrosis Factor, Type I (genetics, metabolism)
• Receptors, Tumor Necrosis Factor, Type II (genetics, metabolism)
• Signal Transduction (drug effects, genetics)