[en] [en] OBJECTIVE: The Fragile X mental retardation (FMR) syndrome is a frequently inherited intellectual disability caused by decreased or absent expression of the FMR protein (FMRP). Lack of FMRP is associated with neuronal degradation and cognitive dysfunction but its role outside the central nervous system is insufficiently studied. Here, we identify a role of FMRP in liver disease.
DESIGN: Mice lacking Fmr1 gene expression were used to study the role of FMRP during tumour necrosis factor (TNF)-induced liver damage in disease model systems. Liver damage and mechanistic studies were performed using real-time PCR, Western Blot, staining of tissue sections and clinical chemistry.
RESULTS: Fmr1null mice exhibited increased liver damage during virus-mediated hepatitis following infection with the lymphocytic choriomeningitis virus. Exposure to TNF resulted in severe liver damage due to increased hepatocyte cell death. Consistently, we found increased caspase-8 and caspase-3 activation following TNF stimulation. Furthermore, we demonstrate FMRP to be critically important for regulating key molecules in TNF receptor 1 (TNFR1)-dependent apoptosis and necroptosis including CYLD, c-FLIPS and JNK, which contribute to prolonged RIPK1 expression. Accordingly, the RIPK1 inhibitor Necrostatin-1s could reduce liver cell death and alleviate liver damage in Fmr1null mice following TNF exposure. Consistently, FMRP-deficient mice developed increased pathology during acute cholestasis following bile duct ligation, which coincided with increased hepatic expression of RIPK1, RIPK3 and phosphorylation of MLKL.
CONCLUSIONS: We show that FMRP plays a central role in the inhibition of TNF-mediated cell death during infection and liver disease.
Disciplines :
Immunology & infectious disease
Author, co-author :
Zhuang, Yuan; Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
Xu, Haifeng C; Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
Shinde, Prashant V; Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
Warfsmann, Jens; Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany
Vasilevska, Jelena; Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
Sundaram, Balamurugan; Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
Behnke, Kristina; Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
Huang, Jun; Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
Hoell, Jessica I; Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany
Borkhardt, Arndt; Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany
Pfeffer, Klaus; Institute of Medical Microbiology and Hospital Hygiene, University Hospital, Heinrich-Heine-University, Düsseldorf, Germany
Taha, Mohamed S; Research on Children with Special Needs Department, Medical research Branch, National Research Centre, Cairo, Egypt ; Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
Herebian, Diran; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Mayatepek, Ertan; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
BRENNER, Dirk ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Immunology and Genetics ; Department of Infection and Immunity, Experimental & Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Department of Dermatology and Allergy Center, Odense Research Center for Anaphylaxis (ORCA), Odense University Hospital, University of Southern Denmark, Odense, Denmark
Ahmadian, Mohammad Reza; Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
Keitel, Verena; Department of Gastroenterology, Hepatology, and Infectious Diseases, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
Wieczorek, Dagmar; Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
Häussinger, Dieter; Department of Gastroenterology, Hepatology, and Infectious Diseases, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
Pandyra, Aleksandra A; Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany ; Department of Gastroenterology, Hepatology, and Infectious Diseases, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
Lang, Karl S; Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany
Lang, Philipp A ; Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany philipp.lang@med.uni-duesseldorf.de
FNR-ATTRACT program Research Committee of the Medical Faculty of the Heinrich-Heine University Düsseldorf German Research Council
Funding text :
Funding this study was supported by the german research council (SFB974, KFO217, la-2558/5-1). Furthermore, this study was supported by the Jürgen Manchot graduate School MOi iii and the research committee of the Medical Faculty of the Heinrich-Heine University Düsseldorf (grant number: 9772690), DB is supported by the Fnr-attract program (a14/BM/7632103).
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