- Author
-
N.A. Otto
- Title
- Immunometabolism in monocytes and macrophages during inflammation and pneumonia
- Supervisors
-
T. van der Poll
- Co-supervisors
-
A.F. de Vos
- Award date
- 26 May 2021
- Number of pages
- 188
- ISBN
- 9789464212952
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
The aim of this thesis is to investigate the role of glucose metabolism in the immune response of monocytes and macrophages during activation and infection (during pneumonia and pneumosepsis). In chapter 2 and 3, we assessed the role of two key mediators in glucose metabolism, LKB1 and HIF1α, in the function of myeloid cells, especially alveolar macrophages, during K. pneumoniae-induced pneumonia and pneumosepsis. LKB1 seems important for the number of alveolar macrophages and therefore host defense. HIF1α depletion affects the TNF production of these cells. In chapter 4, we repurposed transcriptomic analysis to determine the immunometabolic pathways important for human alveolar macrophage activation by LPS. In this and the previous chapters we provide evidence for the finding that murine and human alveolar macrophages do not induce glycolysis upon activation. The effect of HIF1α-stabilization on stimulated monocytes and macrophages is described in chapter 5. Here we show that human monocytes respond differently to this than macrophages. Chapter 6 is dedicated to the effect of adherence on the function and metabolic changes that occur in activated monocytes. We found that adherent monocytes were more anti-inflammatory but induced glycolysis upon stimulation. While nonadherent monocytes produced more inflammatory cytokines, they did not induce glycolysis upon stimulation. The metabolic adaptation of circulating monocytes from patients with pneumonia are described in chapter 7. Here we show that monocytes from pneumonia-patients contain more intracellular pyruvate and α-ketoglutarate and that intracellular pyruvate levels correlate with the cytokine production capacity of these cells.
- Persistent Identifier
- https://hdl.handle.net/11245.1/6f7dbc4e-0c2b-405c-9d64-66c63346cfbb
- Downloads
-
Thesis (complete)
Front matter
Chapter 1: General introduction
Chapter 2: Association of myeloid liver kinase B1 depletion with a reduction in alveolar macrophage numbers and an impaired host defense during gram-negative pneumonia
Chapter 3: Hypoxia-inducible factor-1α in macrophages, but not in neutrophils, is important for host defense during K. pneumoniae-induced pneumosepsis
Chapter 4: Metabolic adaptations of human alveolar macrophages upon activation by lipopolysaccharide in vivo
Chapter 5: Effect of prolyl hydroxylase-2 inhibition on hypoxia inducible factor-1α mediated glycolysis and cytokine production by monocytes and macrophages
Chapter 6: Adherence affects monocyte innate immune function and metabolic reprogramming after lipopolysaccharide stimulation
Chapter 7: Elevated intracellular pyruvate levels correlate with a partially maintained cytokine production capacity in tolerant monocytes from patients with community-acquired pneumonia
Chapter 8: Summary & Nederlandse samenvatting
Chapter 9: General discussion
PhD portfolio; Contributors; Publications; About the author; Acknowledgements/Dankwoord
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