title: Enhancing remyelination through modulation of phagocytosis and lipid recycling
Creators: name: Wuerch, Emily Claire
Publisher: name: Graduate Studies
Year: 2025
Subjects: subject: Neuroscience
subject: Immunology
subject: FOS: Clinical medicine

description: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), characterized by demyelination and neurodegeneration. MS pathology also includes the presence of inhibitory myelin debris. Current MS therapies primarily target inflammatory processes, such as immune cell infiltration, but fail to directly promote remyelination, representing a significant gap in treatment. Previous research has shown that niacin (vitamin B3) can promote remyelination in the lysolecithin-induced demyelination model by enhancing the phagocytic clearance of inhibitory myelin debris by macrophages and microglia. However, its therapeutic potential in experimental autoimmune encephalomyelitis (EAE), an inflammatory MS model, was previously unexplored. In the first part of my thesis, I tested the hypothesis that niacin administration could ameliorate EAE-induced clinical disability and neuropathology through immune modulation and enhanced remyelination. We found that niacin inconsistently ameliorated EAE clinical disease scores, and failed to promote remyelination. We propose that these outcomes may stem from the inability of niacin to modulate lymphocyte activity, a key driver of EAE pathology. Building on this work, I began investigating lipid recycling from foamy macrophages, as evidence suggests that microglia may be a source of cholesterol for oligodendrocytes during remyelination. Following demyelination, macrophages engulf myelin debris, including lipids, and develop a foamy, lipid-laden phenotype, characterized by increased inflammation and diminished capacity to clear additional toxic debris. We investigated strategies to improve phagocytosis and lipid recycling, hypothesizing that promoting lipid export from foamy macrophages could enhance neuronal and oligodendrocyte survival and facilitate remyelination. To test this hypothesis, we first characterized myelin phagocytosis by human and murine microglia and macrophages, and generated foamy macrophages through chronic exposure to myelin and inflammatory cytokines. To enhance lipid export, we treated foamy macrophages with cyclodextrins, compounds known to promote lipid clearance in other disease models. In collaboration with our chemistry team, we tested both a standard commonly-used commercial cyclodextrin and novel formulations. We also used the lysolecithin demyelination model to assess the therapeutic potential of cyclodextrins in an animal model of multiple sclerosis. Cyclodextrins facilitated lipid export from foamy macrophages in culture, and promoted a beneficial macrophage phenotype in lysolecithin lesions. Cyclodextrins also preserved axons and increased the presence of oligodendrocyte lineage cells in lesions. In conclusion, cyclodextrins offer a promising therapeutic strategy for people with MS by enhancing oligodendrocyte cell number and reducing neurodegeneration, addressing limitations of current therapies. Overall, this thesis explores several novel therapeutic approaches to modulate lipid metabolism and myelin debris clearance in MS, with the overarching goal of advancing remyelination therapies.