Diversity of microglia Their contribution to multiple sclerosis lesion formation

Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by myelin loss and axonal damage that leads to lesion formation. Microglia are key players in MS pathology as they play a role in demyelination and inflammation. In this thesis we showed that the profile of human microglia isolated from post-mortem brain tissue can reliably be studied in order to identify microglial specific characteristics in relation with neuropathology. Subsequently, microglia are already involved in myelin processing in normal-appearing white matter (NAWM) MS tissue, devoid of MS lesions. Furthermore, microglia showed a region-specific profile, that differs between cortical grey and white matter regions. Microglial clusters, which can appear in NAWM MS tissue, might be the start of lesion formation. They form a heterogenous population and several clusters showed signs of demyelination and reside in an inflammatory environment, consisting of antibodies, T and B cells. In normal-appearing MS tissue, microglia are in a homeostatic state and isolated microglia are tolerogenic to classic immune stimuli. We provide evidence that antibodies, present on MS myelin, act as an additional stimulus and break microglial immune tolerance. In active MS lesions, microglia highly expressed proteins related to phagocytosis and myelin processing, but they do not secrete inflammatory cytokines and infiltrating macrophages are hardly present. Furthermore, demyelination already takes place around chronic active MS lesions, suggesting that they are expanding. Microglia are an interesting target to treat MS; by blocking pro-inflammation and promoting their phagocytic and regenerative capacities, formation of new MS lesion might be prevented.