Ursula R Sorg1, Kristina Behnke2, Daniel Degrandi1, Maria Reich3, Verena Keitel3, Diran Herebian4, René Deenen5, Marc Beyer6, Joachim L Schultze6, Karl Köhrer5, Helmut E Gabbert7, Ertan Mayatepek4, Dieter Häussinger3, Klaus Pfeffer8. 1. Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany. 2. Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany; Molecular Medicine II, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany. 3. Department of Internal Medicine, Gastroenterology, Hepatology and Infectious Diseases, University Children's Hospital, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany. 4. Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany. 5. Center for Biological and Medical Research, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany. 6. Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany. 7. Institute of Pathology, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany. 8. Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany. Electronic address: Klaus.pfeffer@hhu.de.
Abstract
BACKGROUND & AIMS: The liver exhibits a unique capacity for regeneration in response to injury. Lymphotoxin-β receptor (LTβR), a core member of the tumor necrosis factor (TNF)/tumor necrosis factor receptor (TNFR) superfamily is known to play an important role in this process. However, the function of LTβR during pathophysiological alterations and its molecular mechanisms during liver regeneration are so far ill-characterized. METHODS: LTβR(-/-) mice were subjected to 70% hepatectomy and liver regeneration capacity, bile acid profiles, and transcriptome analysis were performed. RESULTS: LTβR(-/-) deficient mice suffered from increased and prolonged liver tissue damage after 70% hepatectomy, accompanied by deregulated bile acid homeostasis. Pronounced differences in the expression patterns of genes relevant for bile acid synthesis and recirculation were observed. LTβR and TNFRp55 share downstream signalling elements. Therefore, LTβR(-/-) mice were treated with etanercept to create mice functionally deficient in both signalling pathways. Strikingly, the combined blockade of TNFRp55 and LTβR signalling leads to complete failure of liver regeneration resulting in death within 24 to 48h after PHx. Transcriptome analysis revealed a marked disparity in gene expression programs in livers of LTβR(-/-) and etanercept-treated LTβR(-/-) vs. wild-type animals after PHx. Murinoglobulin 2 was identified as a significantly differentially regulated gene. CONCLUSIONS: LTβR is essential for efficient liver regeneration and cooperates with TNFRp55 in this process. Differences in survival kinetics strongly suggest distinct functions for these two cytokine receptors in liver regeneration. Failure of TNFR and LTβR signalling renders liver regeneration impossible.
BACKGROUND & AIMS: The liver exhibits a unique capacity for regeneration in response to injury. Lymphotoxin-β receptor (LTβR), a core member of the tumor necrosis factor (TNF)/tumor necrosis factor receptor (TNFR) superfamily is known to play an important role in this process. However, the function of LTβR during pathophysiological alterations and its molecular mechanisms during liver regeneration are so far ill-characterized. METHODS: LTβR(-/-) mice were subjected to 70% hepatectomy and liver regeneration capacity, bile acid profiles, and transcriptome analysis were performed. RESULTS: LTβR(-/-) deficient mice suffered from increased and prolonged liver tissue damage after 70% hepatectomy, accompanied by deregulated bile acid homeostasis. Pronounced differences in the expression patterns of genes relevant for bile acid synthesis and recirculation were observed. LTβR and TNFRp55 share downstream signalling elements. Therefore, LTβR(-/-) mice were treated with etanercept to create mice functionally deficient in both signalling pathways. Strikingly, the combined blockade of TNFRp55 and LTβR signalling leads to complete failure of liver regeneration resulting in death within 24 to 48h after PHx. Transcriptome analysis revealed a marked disparity in gene expression programs in livers of LTβR(-/-) and etanercept-treated LTβR(-/-) vs. wild-type animals after PHx. Murinoglobulin 2 was identified as a significantly differentially regulated gene. CONCLUSIONS: LTβR is essential for efficient liver regeneration and cooperates with TNFRp55 in this process. Differences in survival kinetics strongly suggest distinct functions for these two cytokine receptors in liver regeneration. Failure of TNFR and LTβR signalling renders liver regeneration impossible.
Authors: Kristina Behnke; Yuan Zhuang; Haifeng C Xu; Balamurugan Sundaram; Maria Reich; Prashant V Shinde; Jun Huang; Nastaran Fazel Modares; Alexei V Tumanov; Robin Polz; Jürgen Scheller; Carl F Ware; Klaus Pfeffer; Verena Keitel; Dieter Häussinger; Aleksandra A Pandyra; Karl S Lang; Philipp A Lang Journal: Hepatology Date: 2018-11-05 Impact factor: 17.425