Berghoff, S. A. et al. (2021) Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis. Nature Neuroscience, 24(1), pp. 47-60. (doi: 10.1038/s41593-020-00757-6) (PMID:33349711) (PMCID:PMC7116742)
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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.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Edgar, Professor Julia |
Authors: | Berghoff, S. A., Spieth, L., Sun, T., Hosang, L., Schlaphoff, L., Depp, C., Düking, T., Winchenbach, J., Neuber, J., Ewers, D., Scholz, P., van der Meer, F., Cantuti-Castelverti, L., Sasmita, A. O., Meschkat, M., Ruhwedel, T., Möbius, W., Sankowski, R., Prinz, M., Huitinga, I., Sereda, M. W., Odoardi, F., Ischebeck, T., Simons, M., Stadelmann-Nessler, C., Edgar, J. M., Nave, K.-A., and Saher, G. |
College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
Research Centre: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology |
Journal Name: | Nature Neuroscience |
Publisher: | Nature Research |
ISSN: | 1097-6256 |
ISSN (Online): | 1546-1726 |
Published Online: | 21 December 2020 |
Copyright Holders: | Copyright © 2020 The Authors |
First Published: | First published in Nature Neuroscience 24(1): 47-60 |
Publisher Policy: | Reproduced in accordance with the publisher copyright policy |
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