小柯机器人

德国马克斯-普朗克研究所Gesine Saher、Klaus-Armin Nave等研究人员合作发现，小胶质细胞通过固醇合成促进脱髓鞘病变修复。这一研究成果于2020年12月21日在线发表在国际学术期刊《自然—神经科学》上。

据研究人员，多发性硬化症（MS）中发炎、脱髓鞘的病变修复需要通过小胶质细胞/巨噬细胞来清除富含胆固醇的髓鞘碎片，并需要从促炎性病变环境转变为消炎性病变环境。随后，少突胶质细胞增加胆固醇水平，这是合成新髓磷脂膜的先决条件。

研究人员假设病变消退受髓磷脂和少突胶质固醇合成的胆固醇命运调节。通过整合基因表达谱、遗传学和全面的表型分析，研究人员发现，矛盾的是，髓磷脂吞噬小胶质细胞/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/巨噬细胞不是产生胆固醇，而是合成了脱氢胆固醇（直接胆固醇前体）。脱氢胆固醇激活肝脏X受体（LXR）信号来解决炎症，为少突胶质细胞的分化创造了宽松的环境。

此外，LXR靶基因产物促进了脂质和胆固醇从载脂小胶质细胞/巨噬细胞的流出，从而支持少突胶质细胞的髓鞘再形成。因此，固醇合成的药理刺激促进了脱髓鞘病变的修复，这提示了MS中髓鞘修复的新疗法。

附：英文原文

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

Author: Stefan A. Berghoff, Lena Spieth, Ting Sun, Leon Hosang, Lennart Schlaphoff, Constanze Depp, Tim Dking, Jan Winchenbach, Jonathan Neuber, David Ewers, Patricia Scholz, Franziska van der Meer, Ludovico Cantuti-Castelvetri, Andrew O. Sasmita, Martin Meschkat, Torben Ruhwedel, Wiebke Mbius, Roman Sankowski, Marco Prinz, Inge Huitinga, Michael W. Sereda, Francesca Odoardi, Till Ischebeck, Mikael Simons, Christine Stadelmann-Nessler, Julia M. Edgar, Klaus-Armin Nave, Gesine Saher

Issue&Volume: 2020-12-21

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. 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.

DOI: 10.1038/s41593-020-00757-6

Source: https://www.nature.com/articles/s41593-020-00757-6

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex