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小胶质细胞通过鲨烯后固醇合成促进脱髓鞘病变的修复。

Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.

机构信息

Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

Institute for Medical Systems Biology, Center for Molecular Neurobiology Hamburg, Hamburg, Germany.

出版信息

Nat Neurosci. 2021 Jan;24(1):47-60. doi: 10.1038/s41593-020-00757-6. Epub 2020 Dec 21.

DOI:10.1038/s41593-020-00757-6
PMID:33349711
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7116742/
Abstract

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.

摘要

修复多发性硬化症（MS）中炎症性、脱髓鞘病变需要小胶质细胞/巨噬细胞清除富含胆固醇的髓磷脂碎片，并将病变环境从促炎转变为抗炎。随后，少突胶质细胞增加胆固醇水平，作为合成新髓鞘膜的前提。我们假设病变的解决取决于受损髓磷脂中胆固醇的命运和少突胶质细胞固醇的合成。通过整合基因表达谱、遗传学和全面表型分析，我们发现，矛盾的是，吞噬髓磷脂的小胶质细胞/巨噬细胞中的固醇合成决定了急性脱髓鞘病变的修复。小胶质细胞/巨噬细胞不是合成胆固醇，而是合成胆固醇的直接前体——鲨烯。鲨烯激活肝 X 受体 (LXR) 信号通路以解决炎症，为少突胶质细胞分化创造了许可环境。此外，LXR 靶基因产物促进富含脂质的小胶质细胞/巨噬细胞中脂质和胆固醇的流出，以支持少突胶质细胞的髓鞘再生。因此，固醇合成的药理学刺激促进了脱髓鞘病变的修复，为 MS 中的髓鞘修复提供了新的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7831/7116742/d654aa09ca43/EMS114908-f007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7831/7116742/d654aa09ca43/EMS114908-f007.jpg

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