Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis
Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis
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DOI：
10.1038/s41593-020-00757-6
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发表时间：
2020-12-21
影响因子：
25
通讯作者：
Saher, Gesine
中科院分区：
文献类型：
--
作者：
Berghoff, Stefan A.;Spieth, Lena;Saher, Gesine
多发性硬化症（MS）中炎症、脱髓鞘病变的修复需要小胶质细胞/巨噬细胞清除富含胆固醇的髓磷脂碎片，并将促炎病变环境转换为抗炎病变环境。随后，少突胶质细胞增加胆固醇水平，这是合成新髓鞘膜的先决条件。我们假设损伤的消退是由受损髓磷脂和少突胶质固醇合成的胆固醇命运调节的。通过整合基因表达谱、遗传学和综合表型，我们发现，矛盾的是，吞噬髓磷脂的小胶质细胞/巨噬细胞中的甾醇合成决定了急性脱髓鞘病变的修复。而不是产生胆固醇，小胶质细胞/巨噬细胞合成去氨甾醇，胆固醇的直接前体。去氨甾醇激活肝脏X受体（LXR）信号来消除炎症，为少突胶质细胞分化创造一个有利的环境。此外，LXR靶基因产物促进脂质和胆固醇从富含脂质的小胶质细胞/巨噬细胞外溢，以支持少突胶质细胞的髓鞘再生。因此，甾醇合成的药理刺激促进了脱髓鞘损伤的修复，这为多发性硬化症髓鞘修复提供了新的治疗策略。脱髓鞘中枢病变的有效修复涉及炎症的解决和髓鞘再生的诱导。Berghoff等人表明，小胶质细胞中的甾醇合成是这两个过程的关键，这可以通过角鲨烯疗法得到支持。
The repair of inflamed, demyelinated lesions as in multiple sclerosis (MS) necessitates the clearance of cholesterol-rich myelin debris by microglia/macrophages and the switch from a pro-inflammatory to an anti-inflammatory lesion environment. Subsequently, oligodendrocytes increase cholesterol levels as a prerequisite for synthesizing new myelin membranes. We hypothesized that lesion resolution is regulated by the fate of cholesterol from damaged myelin and oligodendroglial sterol synthesis. By integrating gene expression profiling, genetics and comprehensive phenotyping, we found that, paradoxically, sterol synthesis in myelin-phagocytosing microglia/macrophages determines the repair of acutely demyelinated lesions. Rather than producing cholesterol, microglia/macrophages synthesized desmosterol, the immediate cholesterol precursor. Desmosterol activated liver X receptor (LXR) signaling to resolve inflammation, creating a permissive environment for oligodendrocyte differentiation. Moreover, LXR target gene products facilitated the efflux of lipid and cholesterol from lipid-laden microglia/macrophages to support remyelination by oligodendrocytes. Consequently, pharmacological stimulation of sterol synthesis boosted the repair of demyelinated lesions, suggesting novel therapeutic strategies for myelin repair in MS.Efficient repair of demyelinated CNS lesions involves the resolution of inflammation and induction of remyelination. Berghoff et al. show that sterol synthesis in microglia is key to both processes, which can be supported by squalene therapy.