Abstract
Microglia are the resident macrophages of the central nervous system (CNS). Like other tissue macrophages, microglia have many different functions under physiological as well as pathological conditions. Microglia can contribute to the initiation, progression and resolution of disease processes and microglia activation is a common hallmark of many CNS diseases.
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By consequence modulation of microglial activation represents an interesting therapeutic strategy. In this thesis, we studied the modulation of microglia activation via different mechanisms and agents. The research presented in this thesis focuses on microglia activation by receptors of the innate immune system known as Toll-like receptors (TLR). TLR-mediated activation can be caused by cellular encounters with microbial ligands (pathogen-associated molecular patterns) as well as by encounters with damaged cell-derived ligands (danger-associated molecular patterns). This broad array of ligands renders it likely that TLR-mediated microglial activation has relevance to various situations where CNS homeostasis is disturbed.
The studies in this thesis have been performed at the Alternatives Unit of the Biomedical Primate Research Centre (BPRC). Our group focuses on the development of in vitro methodology that can be used to reduce, refine or replace in vivo animal experiments. For the research presented in this thesis, we used primary microglia cultures derived from healthy adult rhesus monkeys (macaca mulatta) as a model for adult human microglia. This model has important advantages in terms of genetic and donor age similarities over the use of microglia derived from embryonic, neonatal or adult in bred rodents. Additionally, advantage over the use of adult human microglia is the total control over ante mortem (disease history, process of dying) and post mortem (post mortem time) conditions. Importantly, no monkeys are sacrificed for the exclusive purpose of initiating primary cell cultures. We use brain tissue that comes available when rhesus monkeys are euthanized e.g. at the end of other experiments to isolate microglia. This procedure is part of the active alternatives program within the BPRC aimed at replacement, reduction and refinement of animal experiments.
The research presented in this thesis describes the modulation of TLR-mediated activation of microglia via a variety of mechanisms and agents. In summary, we characterized the effect of different differentiation regimes and anti-inflammatory cytokines on microglia function and TLR-responses. Next to this, we describe new mechanisms that play a role in the initiation and termination of microglia activation via adenosine receptors, which may represent interesting targets in the modulation of microglia activation in CNS disease. Additionally, we demonstrate unanticipated effects of statins on innate immune responses of microglia, by which we may have identified potential adverse effects of statins in their use in CNS disorders with an inflammatory component such as multiple sclerosis. In conclusion, the studies in this thesis contribute to fundamental knowledge on microglia activation and TLR-mediated activation in general, and have resulted in several interesting new leads for future development of human therapeutic strategies.
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