Myelin debris uptake by macrophages and microglia: Resolution of foam cells with a series of novel cyclodextrins

Foamy, lipid-laden macrophages are found in multiple sclerosis (MS) lesions, resulting from excessive phagocytosis of myelin debris following demyelination. These lipid-laden macrophages exhibit an inflammatory phenotype, inhibit remyelination, and likely contribute to MS pathology, yet effective therapeutic strategies to target them are lacking. In this study, we sought to better characterize the temporal patterns of myelin debris phagocytosis by human and murine microglia/macrophages, and generate an in vitro model of foamy phagocytes. In addition, given their demonstrated ability to promote lipid efflux in models of other neurological diseases, we investigated cyclodextrins as potential therapeutic agents in MS. We hypothesized that cyclodextrins could lower the accumulation of lipids in foamy macrophages, potentially modulating their inflammatory phenotype. Several in house-synthesized cyclodextrins were evaluated. We found that prolonged application of myelin and inflammatory cytokines produced an inflammatory macrophage phenotype with an MS-like signature, as determined through bulk sequencing analysis. When particular cyclodextrins were applied to these foamy macrophages in culture, there was reduced accumulation of ingested and processed lipids, and altered expression of genes related to inflammatory pathways or wound healing. Our findings suggest that cyclodextrins may modulate the phenotype of inflammatory macrophages, typical of MS pathology, and hold therapeutic potential in MS, warranting further investigation.