Public Defence: Jonas Aakre Wik
MSc Jonas Aakre Wik at Institute of Clinical Medicine will be defending the thesis “Metabolic characterization of endothelial and CD4+ T cells in immune activation” for the degree of PhD (Philosophiae Doctor).
Due to copyright reasons, an electronic copy of the thesis must be ordered from the faculty. In order for the faculty to have time to process the order, it must be received by the faculty no later than 2 days prior to the public defence. Orders received later than 2 days before the defence will not be processed. Inquiries regarding the thesis after the public defence must be addressed to the candidate.
Trial Lecture – time and place
See Trial Lecture.
- First opponent: Professor Niels Riksen, Radboud University Medical Center, The Netherlands
- Second opponent: Researcher Sigrid Skånland, Oslo University Hospital
- Third member and chair of the evaluation committee: Professor Erik Dissen, University of Oslo
Chair of the Defence
Associate Professor Maja Elstad, University of Oslo
Researcher Johanna Hol Fosse, Oslo University Hospital
Inflammation is a part of the immune response towards harmful stimuli, including infection or damage. Inflammation is characterized by activation of several signaling pathways, and recently by a range of metabolic adaptations.
The primary aim of this thesis was to study the how metabolism in endothelial and T helper cells (Th) is changed upon immune activation.
Measuring uptake and metabolism of radiolabeled glucose revealed that interleukin-1β (IL-1 β)-stimulation increased glucose uptake and combustion despite decreasing proliferation in endothelial cells. This was correlated with increased extracellular acidification and expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Despite this, lactic acid secretion was unaffected. As oxygen consumption was increased, this indicates that IL-1β-stimulation increases mitochondrial pyruvate metabolism. Notably, donor heterogeneity was observed, which may be important for therapeutic efficacy of metabolic inhibitors.
It was further revealed that the PFKFB3 inhibitor 3PO reduced IL-1β-induced activation of inflammatory signaling pathways and expression of adhesion molecules in endothelial cells. However, this effect was not reproduced by alternative methods of inhibiting PFKFB3, indicating that this effect was not mediated by PFKFB3 inhibition.
Lastly, Th-cell proliferation and viability was shown to require the presence of glutamine in both normoxia and hypoxia. It was demonstrated by mass spectrometry that depletion of glutamine or blocking glutamine metabolism was shown to cause depletion of several endogenous amino acids, as well as reduce oxygen consumption. Blocking glutamine metabolism also resulted in reduced rate of glycolysis, mediated by reduced activity of hexokinase.
Overall, these results show that metabolic reprograming is crucial for the immune response, indicating that metabolism may offer a novel strategy for targeting pathological inflammation.
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