The public defence will be held as a video conference over Zoom.
The defence will follow regular procedure as far as possible, hence it will be open to the public and the audience can ask ex auditorio questions when invited to do so.
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Digital Trial Lecture - time and place
Adjudication committee
- First opponent: Professor Ines Heiland, UiT – The Arctic University of Norway, Tromsø
- Second opponent: Researcher Pablo Pelegrin, BioMedical Research Institute of Murcia, Spain
- Third member and chair of the evaluation committee: Associate Professor Thomas Sæther, Institute of Basic Medical Sciences, University of Oslo
Chair of defence
Professor Emeritus Ingvar Jarle Vaage, Institute of Clinical Medicine, University of Oslo
Principal Supervisor
Senior Researcher Øystein Sandanger, Department of Rheumatology, Dermatology and Infectious Diseases, Oslo University Hospital
Summary
Inflammation depends on pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs) which sense molecular patterns associated by microbes and cellular damage. TLR4 and NLRP3 are two well-characterized PRRs. TLR4 induces transcription of pro-inflammatory cytokines while NLRP3 forms inflammasomes that mediate activation and release of IL-1β. Inflammation is closely linked to metabolism as it requires both energy and synthesis of new molecules. The studies presented in this thesis addressed the following questions: Does NAD+ levels affect TLR4 function? Does autophagy regulate TLR4/NLRP3-dependent IL-1β secretion from cardiac fibroblasts? Is CD38 (a NAD+ dependent Ca2+mobilizing enzyme) implicated NLRP3 activation in monocytes and macropahges?
Human primary monocytes were treated with FK866, a NAD+ synthesis inhibitor, leading to a NAD+ depletion which significantly down-regulated TLR4-depednent cytokine synthesis. Further proteomic analysis showed that FK866 inhibited phosphorylation of several proteins involved in the TLR4 signal pathway, which could be rescued by replenishing NAD+ with nicotinamide riboside (NR).
Serum starvation of cardiac fibroblasts profoundly reduced TLR4-induced pro-IL-1β protein levels while TNF, IL-6 and inflammasomes proteins were not affected. Surprisingly, the mTOR inhibitor rapamycin increased pro-IL-1β protein levels while the autophagy inhibitor chloroquine induced pro-IL-1β protein degradation. Both serum starvation and chloroquine increased general protein ubiquitination, suggesting that mTOR regulates pro-IL-1β degradation in cardiac fibroblasts through proteasomes but not autophagy.
Human monocytes and macrophages were treated with CD38 inhibitors which significantly attenuated IL-1β release upon NLRP3 inflammasome activation and suppressed Ca2+ flux induced by NLRP3 activators. These findings support that CD38 promote NLRP3 activity by increasing cytosolic Ca2+ levels.
Additional information
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