Titel: Role of Myeloid Pyruvate Kinase Isoform M2 (PKM2) in Homeostasis and Acute Liver Inflammation
Sonstige Titel: Rolle der myeloischen Pyruvatkinase-Isoform M2 in Homöostase und in der akuten Leberentzündung
Sprache: Englisch
Autor*in: Weltzsch, Jan Philipp
Schlagwörter: PKM2; Myeloid cells; ConA hepatitis
GND-Schlagwörter: HepatitisGND
Concanavalin AGND
Erscheinungsdatum: 2021
Tag der mündlichen Prüfung: 2022-03-22
Myeloid metabolism has emerged as a critical determinant of the innate immune system’s capacity. Granulocytes, monocytes and macrophages as the immunological frontline not only have to quickly identify pathogens and endogenous alarmins but also to react and to contain the inflammatory stimulus, thus preventing pathogen dissemination and avoiding an unrestrained immune response, both of which pose a vital threat to the host organism. Myeloid cells are able to regulate their effector functions via metabolic regulation that is required to initiate innate and adaptive immune responses. Glycolysis as a gateway for carbon compounds is located at the very center of oxidative and anaerobic metabolic pathways. Posttranslational modifications of glycolytic enzymes and their cognate expression levels enable the cell to rapidly regenerate ATP without time-consuming induction of oxidative metabolism while simultaneously providing intermediate compounds for the production of effector molecules. In this context, the role of PKM2 in myeloid cells was investigated. An incomplete Cre-mediated knockdown in macrophages exposed disturbances in the equilibrium of PKM2 oligomers by inducing PKM2 dimerization and upregulating PKM1. Pkm2∆myel macrophages exhibited a more pro-inflammatory M1 phenotype in vitro and showed an increased metabolic flux through glycolysis and oxidative respiration. However, they did not show signs of impaired or altered M2 macrophage polarization. Untreated 12 week old Pkm2∆myel mice presented characteristics of a beginning metabolic syndrome with elevated body and liver weight, hypercholesterolemia and accumulation of plasmatic long-chain acylcarnitines as well as aberrations in key metabolic players of hepatic metabolism, also indicating an early developmental stage of fatty liver disease. Pkm2∆myel mice showed increased numbers of CD11b+ Ly6C+ monocytes in their bone marrow, spleen and liver, as well as a reduced number of hepatic CD4+ cells with a reduced CD4:CD8 ratio. Induction of acute immune-mediated hepatitis via ConA injection lead to an exacerbated liver damage in Pkm2∆myel mice with elevated serum ALT levels and myeloid infiltration, which was accompanied by an aggravated production of M1-like cytokines like IL-1β, CCL2 and IL-23 and a metabolic switch in the hepatic parenchyma towards aerobic glycolysis. Pharmacological activation of PKM2 by TEPP-46 ameliorated ConA-induced acute hepatitis and reduced the transcription of genes related to M1 macrophage polarization and inflammation, such as Ccl2, Il1β and Il23. Also, TEPP-46 reduced Nlrp3 transcription, activation of Caspase-1 and release of HMGB-1 suggesting a role of myeloid PKM2 in the activation of the NLRP3 inflammasome. In conclusion, this study confirms the previously proposed role of myeloid pyruvate kinases in macrophage effector function and expands its significance for the development and perpetuation of murine immune-mediated
hepatitis and metabolic disorders.
URL: https://ediss.sub.uni-hamburg.de/handle/ediss/9581
URN: urn:nbn:de:gbv:18-ediss-100159
Dokumenttyp: Dissertation
Betreuer*in: Horst, Andrea Kristina
Enthalten in den Sammlungen:Elektronische Dissertationen und Habilitationen

Dateien zu dieser Ressource:
Datei Beschreibung Prüfsumme GrößeFormat  
Dissertation.pdff596133ab8c7439f733e26a5b3d0e2a18.01 MBAdobe PDFÖffnen/Anzeigen
Zur Langanzeige



Letzte Woche
Letzten Monat
geprüft am 31.03.2023


Letzte Woche
Letzten Monat
geprüft am 31.03.2023

Google ScholarTM