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

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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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
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 (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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172410The role of the myelinic channel in axonal supportJulia EdgarMultiple Sclerosis Society (MS)38III - Immunology