Impact of myelin phagocytosis on human myeloid cells and its effect on human oligodendrocytes

Abstract Multiple sclerosis is characterized by immune-mediated myelin destruction, leading to oligodendrocyte loss and neuronal degeneration. While remyelination can mitigate myelin loss, this process often fails in the Multiple sclerosis lesions. The underlying cellular and molecular mechanisms of remyelination failure in Multiple sclerosis remain elusive. Results from experimental models suggested that myelin phagocytosis shifts myeloid cells from a pro- to a more anti-inflammatory phenotype thus promoting myelin repair; however, in aged animals myelin debris clearance and remyelination is impaired, at least partially due to an impaired cholesterol degradation. In this study, we investigated the link between remyelination, myelin debris clearance and lipid droplet formation and how myelin uptake influences the inflammatory phenotype of primary human phagocytes using Multiple sclerosis tissue samples, primary human myeloid cells and human induced pluripotent stem cell derived oligodendrocytes. In Multiple sclerosis tissue samples, no correlation was found between the formation of lipid droplets and remyelination. In vitro, macrophages from healthy individuals phagocytosing control myelin inhibited oligodendrocyte differentiation despite switching from a pro- to anti-inflammatory phenotype independent of lipid droplets. Macrophages from people with Multiple sclerosis, autoimmune encephalitis or stroke phagocytosed myelin similar to macrophages from healthy individuals, but did not upregulate cytokine secretion and had no effect on oligodendroglial differentiation. In contrast, macrophages phagocytosing Multiple sclerosis myelin overcame this silenced phenotype and their supernatants impaired oligodendroglial differentiation. In summary, we examine here the formation, abundance and localization of perilipin positive lipid droplets in myeloid cells and their correlation with remyelination in Multiple sclerosis lesions. Furthermore, our in vitro data suggest that myelin-phagocytosing myeloid cells impair oligodendroglial differentiation regardless of their inflammatory phenotype. Additionally, they demonstrate the importance of myelin alterations in driving inflammation as well as impaired oligodendroglial differentiation and highlight the presence of significant differences between Multiple sclerosis and its animal models.