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

Autor: Lena Spieth, Roman Sankowski, David Ewers, Martin Meschkat, Stefan A. Berghoff, Mikael Simons, Jan Winchenbach, Ting Sun, Julia M. Edgar, Gesine Saher, Torben Ruhwedel, Ludovico Cantuti-Castelvetri, Christine Stadelmann-Nessler, Franziska van der Meer, Francesca Odoardi, Wiebke Möbius, Tim Düking, Klaus-Armin Nave, Michael W. Sereda, Patricia Scholz, Constanze Depp, Lennart Schlaphoff, Marco Prinz, Jonathan Neuber, Andrew Octavian Sasmita, Inge Huitinga, Till Ischebeck, Leon Hosang
Přispěvatelé: Netherlands Institute for Neuroscience (NIN)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
metabolism [Desmosterol]
chemistry.chemical_compound
Myelin
Mice
0302 clinical medicine
Desmosterol
Liver X Receptors
metabolism [Inflammation]
metabolism [Liver X Receptors]
Microglia
Chemistry
General Neuroscience
Middle Aged
Cell biology
Oligodendroglia
Sterols
medicine.anatomical_structure
Cholesterol
Nr1h3 protein
mouse
Female
lipids (amino acids
peptides
and proteins)
medicine.symptom
Squalene
Encephalomyelitis
Autoimmune
Experimental
Multiple Sclerosis
Inflammation
Article
Lesion
metabolism [Oligodendroglia]
03 medical and health sciences
Phagocytosis
medicine
Animals
Humans
metabolism [Squalene]
ddc:610
Remyelination
Liver X receptor
pathology [Inflammation]
biosynthesis [Sterols]
Gene Expression Profiling
Oligodendrocyte differentiation
metabolism [Cholesterol]
Lipid Metabolism
physiology [Microglia]
Mice
Inbred C57BL
030104 developmental biology
nervous system
pathology [Demyelinating Diseases]
Neuroscience
030217 neurology & neurosurgery
Demyelinating Diseases
Zdroj: Nature Neuroscience, 24, 47-60. Nature Publishing Group
Nature neuroscience.
Nature neuroscience 24(1), 47-60 (2021). doi:10.1038/s41593-020-00757-6
Nature neuroscience
ISSN: 1097-6256
DOI: 10.1038/s41593-020-00757-6
Popis: 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.
Databáze: OpenAIRE
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