Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.
Animals
Cholesterol
/ metabolism
Demyelinating Diseases
/ pathology
Desmosterol
/ metabolism
Encephalomyelitis, Autoimmune, Experimental
Female
Gene Expression Profiling
Humans
Inflammation
/ metabolism
Lipid Metabolism
Liver X Receptors
/ metabolism
Mice
Mice, Inbred C57BL
Microglia
/ physiology
Middle Aged
Multiple Sclerosis
Oligodendroglia
/ metabolism
Phagocytosis
Squalene
/ metabolism
Sterols
/ biosynthesis
Journal
Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
27
04
2020
accepted:
12
11
2020
pubmed:
23
12
2020
medline:
9
3
2021
entrez:
22
12
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33349711
doi: 10.1038/s41593-020-00757-6
pii: 10.1038/s41593-020-00757-6
pmc: PMC7116742
mid: EMS114908
doi:
Substances chimiques
Liver X Receptors
0
Nr1h3 protein, mouse
0
Sterols
0
Desmosterol
313-04-2
Squalene
7QWM220FJH
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
47-60Subventions
Organisme : European Research Council
ID : 204034
Pays : International
Organisme : European Research Council
ID : 269020
Pays : International
Organisme : Multiple Sclerosis Society
ID : 38.0
Pays : United Kingdom
Organisme : National Centre for the Replacement, Refinement and Reduction of Animals in Research
ID : NC/L000423/1
Pays : United Kingdom
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