Sepsis is a complex disorder caused by a maladaptive host response to an infection, leading to acute organ dysfunction and consequent high risk of death. It is the leading cause of mortality in intensive care units and the third cause of overall hospital mortality. Despite extensive research, the pathophysiology of sepsis remains poorly understood. New insights into its molecular bases can provide the urgently needed novel therapies for sepsis. Hallmarks of
sepsis include an acute burst in pro-inflammatory production and reprogramming of basic metabolic pathways. In this thesis, we study the role of two different pathways in the progression of sepsis. In the first part of this thesis, we studied the role of tumor necrosis factor receptor 1 (TNFR1)
in sepsis (chapter 3.1.). TNF is a pleiotropic cytokine with pro-inflammatory as well as immunomodulatory functions. Aberrant TNF levels are found in sepsis patients, nonetheless, the use of pan-TNF inhibition is highly contested. We and others believe that TNFR1 targeting is a much more promising strategy to combat inflammation than a full TNF blockade. Proofof-concept has been demonstrated by our research group in the context of Alzheimer’s disease and multiple sclerosis. The therapeutic potential of TNFR1 blockade in sepsis is however controversial. We hypothesize that TNFR1 signaling has a dual role in sepsis, namely a mediating role via its pro-inflammatory effects and a protective role via its anti-bacterial function. Uncoupling the harmful from the beneficial effects of TNFR1 signaling in sepsis could be of therapeutic benefit. Therefore, we aimed to identify the cell type mediating the devastating effects of TNF/TNFR1 signaling in sepsis using conditional TNFR1KO mice. We studied KO in hepatocytes, endothelium and intestinal epithelium because these cell types have been shown to play a role in sepsis. However, none of the tested conditional knockout mice showed improved survival in our murine sepsis model. Conversely, we generated bone marrow chimeric mice that lack TNF/TNFR1 signaling in all the cells, except for their myeloid cells, as myeloid TNF/TNFR1 signaling is essential for resisting infection. Again, we were not able to find a significant protection in our murine sepsis model. In the second part of this thesis, we set out to identify the role of glucocorticoid (GC) signaling in sepsis (chapter 3.2.). GCs are used to treat a wide variety of infammatory diseases owing to
their anti-inflammatory capacity, however, their role in sepsis is controversial. In the current study, we demonstrate that sepsis quickly induces a status of GC resistance, at the level of reduced GR-DNA binding. We believe that the consequences of GC resistance in sepsis are twofold. On the one hand, obviously no therapeutic, anti-inflammatory effects can be expected from exogenous GCs administered under such a condition. On the other hand, physiological functions of endogenously produced GCs are failing. Next to the expected effect of endogenous GC signaling to limit the exaggerated immune response, we here identify a role for GR in tolerating high lactate levels. Lactate is a reliable indicator of illness severity and higher levels are predictive for increased mortality. Nonetheless, the precise role of lactate in sepsis is still laregely unclear. We observed that administration of high doses of lactate are not toxic in healthy animals, but in combination with GR signaling deficiency (introduced pharmacologically with RU486, genetically in GRdim/dim mice or surgically via adrenalectomized mice), lactate induces acute lethality. This lethality is a consequence of increased VEGF levels in the plasma, vascular leakage, hypotension, and ultimately fatal organ damage. In conclusion, sepsis leads to GR failure and hyperlactatemia, which collectively leads to a lethal
vascular collapse. Overall, we investigated the role of TNFR1 and GC signaling in sepsis. The findings in this thesis contribute to the understanding of the molecular bases of sepsis and provide new insights that might inspire the development of novel therapeutics in sepsis.