Thesis defense Suus Bongers

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In this thesis we explore the role of neutrophils, particularly their subsets, in various inflammatory conditions, including severe trauma, experimental human endotoxemia and COVID-19. Neutrophils, key players in the immune response, exhibit dynamic changes in both form and function depending on the stage and type of inflammation. This is crucial knowledge for understanding immune responses and optimizing clinical strategies.

We revealed that neutrophil composition in the bloodstream varies significantly across acute, sub-acute, and chronic inflammation. In acute conditions, the CD16dim (banded) subset predominates, while in sub-acute inflammation, CD62Ldim (hypersegmented) neutrophils increase. Functionally, neutrophil subsets exhibit distinct abilities in tasks like chemotaxis, phagocytosis, intracellular acidification and bacterial killing of pathogens. For example, the CD16dim subset shows optimal bacterial killing during acute inflammation, while the CD62Ldim subset structurally demonstrates reduced intracellular killing capacity. We hypothesize that these functional difference might be due to a shift towards a “ROS-prone” phenotype of the CD62Ldim subset. The reduced ability to kill bacteria intracellularly, along with the proposed increase in reactive oxygen species (ROS) production, suggests that the CD62Ldim subset may play a regulatory role instead of an antibacterial role. The CD62Ldim subset may therefore contribute to increased infection risk, especially in critically ill patients.

The expression profiles of neutrophil markers, including CD16, CD62L, CD10 and CD64, offer insights into neutrophil behavior and offer clinical potential. Rapid changes in these markers can predict the severity of inflammation, with CD10’s slow return to baseline potentially serving as a biomarker for monitoring inflammation resolution. Furthermore, the thesis explores the diagnostic potential of neutrophil markers like CD64 to predict the presence of bacterial infections in the ED. In addition we also assessed intracellular effects of several antibiotics on S. aureus inside of human neutrophils which is especially relevant for the CD62Ldim neutrophils, as they may act as “Trojan horses” spreading infection. These studies underscore the clinical relevance of studying neutrophils in diagnosing and treating infections.

Overall, this work advances our understanding of neutrophil dynamics and their functional adaptations. This provides valuable insights for improving diagnostic, therapeutic and infection management strategies in various inflammatory diseases such as severe traumatic injury.