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

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

doi:10.1038/s41593-020-00757-6

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

MPS-Authors

/persons/resource/persons202532

Berghoff, Stefan A.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons213399

Spieth, Lena
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons270577

Sun, Ting
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons232123

Schlaphoff, Lennart
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons229789

Depp, Constanze
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons202530

Düking, Tim
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons202528

Winchenbach, Jan
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

Neuber, Jonathan
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons224794

Ewers, David
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons271994

Sasmita, Andrew O.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons173772

Meschkat, Martin
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182382

Ruhwedel, Torben
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182306

Möbius, Wiebke
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182406

Sereda, Michael Werner
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182137

Edgar, Julia M.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182320

Nave, Klaus-Armin
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182386

Saher, Gesine
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

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引用

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-Castelvetri, 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., & Saher, G. (2021). Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis. Nature Neuroscience, 24, 47-60. doi:10.1038/s41593-020-00757-6.

引用: https://hdl.handle.net/21.11116/0000-000D-1EEE-7

要旨

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.