Home > Publications Database > Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis. > print

001     155681
005     20230915092336.0
024 7 _ |a 10.1038/s41593-020-00757-6
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024 7 _ |a pmid:33349711
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024 7 _ |a pmc:PMC7116742
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024 7 _ |a 1097-6256
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024 7 _ |a 1546-1726
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037 _ _ |a DZNE-2021-00849
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Berghoff, Stefan A
|b 0
245 _ _ |a Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.
260 _ _ |a New York, NY
|c 2021
|b Nature America
336 7 _ |a article
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336 7 _ |a ARTICLE
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520 _ _ |a 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.
536 _ _ |a 351 - Brain Function (POF4-351)
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650 _ 7 |a Liver X Receptors
|2 NLM Chemicals
650 _ 7 |a Nr1h3 protein, mouse
|2 NLM Chemicals
650 _ 7 |a Sterols
|2 NLM Chemicals
650 _ 7 |a Desmosterol
|0 313-04-2
|2 NLM Chemicals
650 _ 7 |a Squalene
|0 7QWM220FJH
|2 NLM Chemicals
650 _ 7 |a Cholesterol
|0 97C5T2UQ7J
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Cholesterol: metabolism
|2 MeSH
650 _ 2 |a Demyelinating Diseases: pathology
|2 MeSH
650 _ 2 |a Desmosterol: metabolism
|2 MeSH
650 _ 2 |a Encephalomyelitis, Autoimmune, Experimental
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Gene Expression Profiling
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Inflammation: metabolism
|2 MeSH
650 _ 2 |a Inflammation: pathology
|2 MeSH
650 _ 2 |a Lipid Metabolism
|2 MeSH
650 _ 2 |a Liver X Receptors: metabolism
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
650 _ 2 |a Microglia: physiology
|2 MeSH
650 _ 2 |a Middle Aged
|2 MeSH
650 _ 2 |a Multiple Sclerosis
|2 MeSH
650 _ 2 |a Oligodendroglia: metabolism
|2 MeSH
650 _ 2 |a Phagocytosis
|2 MeSH
650 _ 2 |a Squalene: metabolism
|2 MeSH
650 _ 2 |a Sterols: biosynthesis
|2 MeSH
700 1 _ |a Spieth, Lena
|0 0000-0002-0308-0144
|b 1
700 1 _ |a Sun, Ting
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700 1 _ |a Hosang, Leon
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700 1 _ |a Schlaphoff, Lennart
|0 0000-0001-8043-4025
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700 1 _ |a Depp, Constanze
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700 1 _ |a Düking, Tim
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700 1 _ |a Winchenbach, Jan
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700 1 _ |a Neuber, Jonathan
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700 1 _ |a Ewers, David
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700 1 _ |a Scholz, Patricia
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700 1 _ |a van der Meer, Franziska
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700 1 _ |a Cantuti-Castelvetri, Ludovico
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700 1 _ |a Sasmita, Andrew O
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700 1 _ |a Meschkat, Martin
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700 1 _ |a Ruhwedel, Torben
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700 1 _ |a Möbius, Wiebke
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700 1 _ |a Sankowski, Roman
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700 1 _ |a Prinz, Marco
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700 1 _ |a Huitinga, Inge
|0 0000-0002-4878-8920
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700 1 _ |a Sereda, Michael W
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700 1 _ |a Odoardi, Francesca
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700 1 _ |a Ischebeck, Till
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700 1 _ |a Simons, Mikael
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700 1 _ |a Stadelmann-Nessler, Christine
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700 1 _ |a Edgar, Julia M
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700 1 _ |a Nave, Klaus-Armin
|0 0000-0001-8724-9666
|b 26
700 1 _ |a Saher, Gesine
|0 0000-0003-3507-9604
|b 27
|e Corresponding author
773 _ _ |a 10.1038/s41593-020-00757-6
|g Vol. 24, no. 1, p. 47 - 60
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|t Nature neuroscience
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856 4 _ |u https://www.nature.com/articles/s41593-020-00757-6
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