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Fragile X mental retardation protein protects against tumour necrosis factor-mediated cell death and liver injury
  1. Yuan Zhuang1,
  2. Haifeng C Xu1,
  3. Prashant V Shinde1,
  4. Jens Warfsmann2,
  5. Jelena Vasilevska1,
  6. Balamurugan Sundaram1,
  7. Kristina Behnke1,
  8. Jun Huang1,
  9. Jessica I Hoell2,
  10. Arndt Borkhardt2,
  11. Klaus Pfeffer3,
  12. Mohamed S Taha4,5,
  13. Diran Herebian6,
  14. Ertan Mayatepek6,
  15. Dirk Brenner7,8,9,
  16. Mohammad Reza Ahmadian5,
  17. Verena Keitel10,
  18. Dagmar Wieczorek11,
  19. Dieter Häussinger10,
  20. Aleksandra A Pandyra1,10,
  21. Karl S Lang12,
  22. Philipp A Lang1
  1. 1 Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
  2. 2 Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany
  3. 3 Institute of Medical Microbiology and Hospital Hygiene, University Hospital, Heinrich-Heine-University, Düsseldorf, Germany
  4. 4 Research on Children with Special Needs Department, Medical research Branch, National Research Centre, Cairo, Egypt
  5. 5 Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
  6. 6 Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  7. 7 Department of Infection and Immunity, Experimental & Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
  8. 8 Department of Dermatology and Allergy Center, Odense Research Center for Anaphylaxis (ORCA), Odense University Hospital, University of Southern Denmark, Odense, Denmark
  9. 9 Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg
  10. 10 Department of Gastroenterology, Hepatology, and Infectious Diseases, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
  11. 11 Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
  12. 12 Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany
  1. Correspondence to Dr Philipp A Lang, Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr 1, Düsseldorf 40225, Germany; philipp.lang{at}med.uni-duesseldorf.de

Abstract

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.

  • liver damage
  • septic shock
  • Fragile X syndrome
  • TNF receptor signaling

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Footnotes

  • KSL and PAL contributed equally.

  • Contributors YZ designed and conducted the experiments and analysed the data. HCX, PVS, JW, JV, BS, KB, JH, JIH, AB and KP conducted the experiment and analysed the data. MST, DH, EM, DB, MRA, VK, DW, DH, AAP and KSL analysed the data. AAP and KSL supervised the study and edited the manuscript. PAL designed the whole project, supervised the study and wrote the manuscript.

  • 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).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Landesamt für Natur, Umwelt und Verbraucherschutz (LANUV), North Rhine-Westphalia, Germany. State Office for Nature, Environment and Consumer Protection.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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