Upon demyelinating injury, microglia orchestrate a regenerative response that promotes myelin repair, thereby restoring rapid signal propagation and protecting axons from further damage. Whereas the essential phagocytic function of microglia for remyelination is well known, the underlying metabolic pathways required for myelin debris clearance are poorly understood. Here, we show that cholesterol esterification in male mouse microglia/macrophages is a necessary adaptive response to myelin debris uptake and required for the generation of lipid droplets upon demyelinating injury. When lipid droplet biogenesis is defective, innate immune cells do not resolve, and the regenerative response fails. We found that triggering receptor expressed on myeloid cells 2 (TREM2)–deficient mice are unable to adapt to excess cholesterol exposure, form fewer lipid droplets, and build up endoplasmic reticulum (ER) stress. Alleviating ER stress in TREM2-deficient mice restores lipid droplet biogenesis and resolves the innate immune response. Thus, we conclude that TREM2-dependent formation of lipid droplets constitute a protective response required for remyelination to occur.

中文翻译：

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髓鞘再生需要吞噬细胞中依赖 TREM2 的脂滴生物发生

在脱髓鞘损伤后，小胶质细胞会协调促进髓鞘修复的再生反应，从而恢复快速信号传播并保护轴突免受进一步损伤。尽管小胶质细胞对髓鞘再生的基本吞噬功能是众所周知的，但对髓鞘碎片清除所需的潜在代谢途径却知之甚少。在这里，我们表明雄性小鼠小胶质细胞/巨噬细胞中的胆固醇酯化是对髓鞘碎片摄取的必要适应性反应，并且是脱髓鞘损伤时产生脂滴所必需的。当脂滴生物发生有缺陷时，先天免疫细胞不会分解，再生反应就会失败。我们发现骨髓细胞 2 (TREM2) 上表达的触发受体 - 缺陷小鼠无法适应过量的胆固醇暴露，形成更少的脂滴，并增加内质网 (ER) 压力。减轻 TREM2 缺陷小鼠的 ER 应激可恢复脂滴生物发生并解决先天免疫反应。因此，我们得出结论，依赖于 TREM2 的脂滴形成构成了发生髓鞘再生所需的保护性反应。