Yu Jian-Bing, Hong Chen, Ren Xue-Wei, Guo Wei, Chen Ye-Fan, Ji Juan, Zhang Xi-Yue, Sun Xiu-Lan
Department 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.).
Nanjing University of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu, China (X.-L.S.).
Stroke. 2025 Jul;56(7):1897-1908. doi: 10.1161/STROKEAHA.124.049745. Epub 2025 Apr 22.
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.
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.
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.
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.
在缺血性白质损伤后，小胶质细胞负责吞噬和降解富含胆固醇的髓磷脂碎片，并将其储存为脂滴。然而，我们对小胶质细胞如何处理这些吞噬物质的了解仍然有限。我们之前的研究发现芬戈莫德（FTY720）是小胶质细胞TREM2（髓系细胞表达的触发受体2）的高亲和力配体。因此，我们旨在揭示靶向TREM2的FTY720在髓鞘再生过程中调节小胶质细胞胆固醇代谢的作用。
通过双侧颈动脉狭窄在雄性野生型和TREM2基因敲除小鼠中诱导慢性缺血性白质损伤。在双侧颈动脉狭窄手术后，每天通过腹腔注射给予FTY720，持续28天。使用行为测试、透射电子显微镜、免疫荧光和生化分析评估认知功能、白质完整性、小胶质细胞中胆固醇和脂滴的积累以及少突胶质细胞分化。体外共培养系统用于评估胆固醇转移和髓鞘再生效果。
FTY720显著减轻了双侧颈动脉狭窄小鼠的认知缺陷并促进了髓鞘再生，这通过莫里斯水迷宫中的表现增强以及透射电子显微镜和免疫荧光观察到的脱髓鞘减少得以证明。这种治疗效果在TREM2基因敲除的双侧颈动脉狭窄小鼠中不存在。机制上，FTY720通过TREM2促进小胶质细胞中ABCA1（ATP结合盒转运蛋白A1）从溶酶体重新分布到细胞膜，这促进了胆固醇外流并减少了细胞内胆固醇和脂滴的积累。此外，体外共培养实验表明，FTY720通过TREM2增强了小胶质细胞向少突胶质细胞的胆固醇转移，从而促进少突胶质细胞髓鞘形成。
我们的研究表明，FTY720通过TREM2调节小胶质细胞中髓鞘源性胆固醇的再循环，为少突胶质细胞提供胆固醇并支持髓鞘再生，从而为缺血性白质损伤提供了一个新的治疗靶点。
