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Published on: February 22, 2015
FTY720 Modulating Microglia-Mediated Cholesterol Recycling via TREM2 Promotes Remyelination Following Ischemic Damage
Jian-Bing Yu1, Chen Hong1, Xue-Wei Ren1
1Department of Pharmacology, Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Jiangsu, China (J.-B.Y., C.H., X.-W.R., W.G., Y.-F.C., J.J., X.-Y.Z., X.-L.S.).
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.
Insights
FTY720 treatment promotes remyelination after ischemic white matter damage by enhancing microglial cholesterol processing via TREM2, improving cognitive function and white matter integrity.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia clear cholesterol-rich myelin debris after ischemic white matter damage, forming lipid droplets.
- The processing of engulfed myelin by microglia remains poorly understood.
- FTY720 is identified as a high-affinity ligand for microglial TREM2 (triggering receptor expressed on myeloid cells 2).
Purpose of the Study:
- To investigate the role of FTY720 targeting TREM2 in regulating microglial cholesterol metabolism during remyelination.
- To assess FTY720's therapeutic potential in ischemic white matter damage.
Main Methods:
- Induction of chronic ischemic white matter damage in mice via bilateral carotid artery stenosis.
- Administration of FTY720 and evaluation of cognitive function, white matter integrity, and microglial lipid accumulation.
- In vitro coculture systems to assess cholesterol transfer and remyelination efficacy.
Main Results:
- FTY720 alleviated cognitive deficits and promoted remyelination in mice with ischemic white matter damage.
- The therapeutic effects of FTY720 were dependent on TREM2 expression.
- FTY720 facilitated microglial cholesterol efflux via TREM2-mediated ABCA1 redistribution and enhanced oligodendrocyte myelination.
Conclusions:
- FTY720 regulates myelin-derived cholesterol recycling in microglia through TREM2.
- This process supplies cholesterol to oligodendrocytes, supporting remyelination.
- FTY720 represents a novel therapeutic target for ischemic white matter damage.
