Dokument: Hepato-protective role of Fragile X Mental Retardation Protein (FMRP) and Immune Cells in Liver Diseases

Titel:	Hepato-protective role of Fragile X Mental Retardation Protein (FMRP) and Immune Cells in Liver Diseases
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=52327
URN (NBN):	urn:nbn:de:hbz:061-20200220-105725-0
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Zhuang, Yuan [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 19,58 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 19.02.2020 / geändert 19.02.2020
Beitragende:	Prof. Dr. med. Lang, Philipp [Gutachter] Prof. Dr. Schaal, Heiner [Gutachter]
Dewey Dezimal-Klassifikation:	600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit
Beschreibung:	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 impaired neuronal development and cognitive dysfunction but its role outside the central nervous system is insufficiently studied. Here, we identify a role of FMRP in liver disease. Fmr1null mice exhibited increased liver damage during virus-mediated hepatitis following infection with the lymphocytic choriomeningitis virus (LCMV). Exposure to Tumor necrosis factor (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 Cylindromatosis (CYLD), short isoform of FLICE-like inhibitory protein (c-FLIPS) and JUN N-terminal kinase (JNK), which contribute to prolonged receptor-interacting serine/threonine-protein kinase 1 (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 experimentally induced acute cholestasis following bile duct ligation, which coincided with increased hepatic expression of RIPK1, RIPK3 and phosphorylation of mixed lineage kinase domain-like protein (MLKL). In conclusion, we show that FMRP plays a central role in the inhibition of TNF-mediated cell death during infection and liver disease. The liver has an extraordinary capacity to regenerate through activation of key molecular pathways. However, central regulators controlling liver regeneration remain insufficiently studied. Here, we show that B cell–deficient animals failed to induce sufficient liver regeneration after partial hepatectomy (PHx). Consistently, adoptive transfer of B cells could rescue defective liver regeneration. B cell–mediated lymphotoxin beta production promoted recovery from PHx. Absence of B cells coincided with loss of splenic CD169 positive (CD169+) macrophages. Moreover, depletion of CD169+ macrophages resulted in defective liver regeneration and decreased survival, which was associated with reduced hepatocyte proliferation. Mechanistically, CD169+ macrophages contributed to liver regeneration by inducing hepatic interleukin‐6 (IL‐6) production and signal transducer and activator of transcription 3 activation. Accordingly, treatment of CD169+ cell–depleted animals with IL‐6/IL‐6 receptor rescued liver regeneration and severe pathology following PHx. In conclusion, we identified CD169+ cells to be a central trigger for liver regeneration, by inducing key signaling pathways important for liver regeneration.
Lizenz:	Urheberrechtsschutz
Fachbereich / Einrichtung:	Medizinische Fakultät » Institute » Institut für Molekulare Medizin
Dokument erstellt am:	20.02.2020
Dateien geändert am:	20.02.2020
Promotionsantrag am:	03.12.2019
Datum der Promotion:	23.01.2020