FTY720 Modulating Microglia-Mediated Cholesterol Recycling via TREM2 Promotes Remyelination Following Ischemic Damage

BACKGROUND: Following ischemic white matter damage, microglia are responsible for phagocytosing and degrading cholesterol-rich myelin debris, storing them as lipid droplets. However, our understanding of how microglia process this engulfed material remains limited. Our previous findings identified fingolimod (FTY720) as a high-affinity ligand for microglial TREM2 (triggering receptor expressed on myeloid cells 2). Therefore, we aimed to reveal the role of FTY720 targeting TREM2 in regulating microglial cholesterol metabolism during remyelination. METHODS: Chronic ischemic white matter damage was induced by bilateral carotid artery stenosis in male wild-type and TREM2 −/− mice. FTY720 was administered daily via intraperitoneal injection for 28 days following bilateral carotid artery stenosis surgery. Cognitive function, white matter integrity, accumulation of cholesterol and lipid droplets in microglia, and oligodendrocyte differentiation were evaluated using behavioral tests, transmission electron microscopy, immunofluorescence, and biochemical analyses. In vitro coculture systems were used to evaluate cholesterol transfer and remyelination efficacy. RESULTS: FTY720 significantly alleviated cognitive deficits and promoted remyelination in bilateral carotid artery stenosis mice, as evidenced by enhanced performance in the Morris water maze and reduced demyelination observed via transmission electron microscopy and immunofluorescence. This therapeutic effect was absent in TREM2 −/− bilateral carotid artery stenosis mice. Mechanistically, FTY720 promoted the redistribution of ABCA1 (ATP-binding cassette transporter A1) from lysosomes to the cell membrane in microglia via TREM2, which facilitated cholesterol efflux and reduced the accumulation of intracellular cholesterol and lipid droplets. Additionally, in vitro coculture experiments revealed that FTY720 enhanced cholesterol transfer from microglia to oligodendrocytes through TREM2, thereby promoting oligodendrocyte myelination. CONCLUSIONS: Our study suggested that FTY720 regulated the recycling of myelin-derived cholesterol from microglia through TREM2, supplying cholesterol to oligodendrocytes and supporting remyelination, thus offering a novel therapeutic target for ischemic white matter damage.