Stephenson Roxan A, Sepulveda Jordy, Johnson Kory R, Lita Adrian, Gopalakrishnan Jaanam, Acri Dominic J, Beilina Alexandra, Cheng Linling, Yang Linda G, Root Jessica T, Ward Michael E, Combs Christian, Skarnes William C, Cookson Mark R, Shih Han-Yu, Larion Mioara, Rebeck G William, Narayan Priyanka S
Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Department of Pharmacology and Physiology, Georgetown University, Washington, DC, USA.
Cell Rep. 2025 Jul 22;44(7):115961. doi: 10.1016/j.celrep.2025.115961. Epub 2025 Jul 10.
Changes to cellular lipids accompany shifts in microglial cell state, but the functional significance of these metabolic changes remains poorly understood. In human induced pluripotent stem cell-derived microglia, we observed that both extrinsic activation (by lipopolysaccharide treatment) and intrinsic triggers (the Alzheimer's disease-associated APOE4 genotype) result in accumulation of triglyceride-rich lipid droplets. We demonstrate that lipid droplet accumulation is not simply concomitant with changes in the cell state. In fact, both triglyceride biosynthesis and catabolism are critical for the activation-induced transcription and secretion of inflammatory cytokines and chemokines, as well as changes in phagocytosis. In microglia harboring the Alzheimer's disease risk APOE4 genotype, inhibiting triglyceride biosynthesis attenuates disease-associated transcriptional states. Triglyceride biosynthesis inhibition also rescues microglial surveillance defects observed in slices from APOE4 humanized transgenic mice. Together, our findings establish that modulating triglyceride metabolism can tune microglial immune activity in response to extrinsic activation and in APOE4-associated disease.
细胞脂质的变化伴随着小胶质细胞状态的转变，但这些代谢变化的功能意义仍知之甚少。在人诱导多能干细胞衍生的小胶质细胞中，我们观察到外在激活（通过脂多糖处理）和内在触发因素（与阿尔茨海默病相关的APOE4基因型）都会导致富含甘油三酯的脂滴积累。我们证明脂滴积累并非简单地与细胞状态变化同时发生。事实上，甘油三酯的生物合成和分解代谢对于激活诱导的炎性细胞因子和趋化因子的转录和分泌，以及吞噬作用的变化都至关重要。在携带阿尔茨海默病风险APOE4基因型的小胶质细胞中，抑制甘油三酯生物合成可减弱疾病相关的转录状态。抑制甘油三酯生物合成还可挽救在APOE4人源化转基因小鼠切片中观察到的小胶质细胞监测缺陷。总之，我们的研究结果表明，调节甘油三酯代谢可以调节小胶质细胞对外在激活和与APOE4相关疾病的免疫活性。
