Stearoyl-CoA desaturase-1 impairs the reparative properties of macrophages and microglia in the brain

Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-r...

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Published in:The Journal of experimental medicine Vol. 217; no. 5
Main Authors: Bogie, Jeroen F J, Grajchen, Elien, Wouters, Elien, Corrales, Aida Garcia, Dierckx, Tess, Vanherle, Sam, Mailleux, Jo, Gervois, Pascal, Wolfs, Esther, Dehairs, Jonas, Van Broeckhoven, Jana, Bowman, Andrew P, Lambrichts, Ivo, Gustafsson, Jan-Åke, Remaley, Alan T, Mulder, Monique, Swinnen, Johannes V, Haidar, Mansour, Ellis, Shane R, Ntambi, James M, Zelcer, Noam, Hendriks, Jerome J A
Format: Journal Article
Language:English
Published: United States 04.05.2020
Subjects:
Animals
ATP Binding Cassette Transporter 1 - metabolism
Brain - pathology
Cell Line
Cholesterol - metabolism
Endocytosis
Fatty Acids - metabolism
Foam Cells - metabolism
Humans
Inflammation - pathology
Macrophages - enzymology
Macrophages - metabolism
Macrophages - ultrastructure
Mice
Microglia - enzymology
Microglia - metabolism
Myelin Sheath - metabolism
Phagocytes - pathology
Phagocytes - ultrastructure
Phenotype
Protein Kinase C-delta - metabolism
Stearoyl-CoA Desaturase - deficiency
Stearoyl-CoA Desaturase - metabolism
ISSN:1540-9538, 1540-9538
Online Access:Get more information
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Summary:Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-resolving phenotype, while sustained intracellular accumulation of myelin induced a lesion-promoting phenotype. This phenotypic shift was controlled by stearoyl-CoA desaturase-1 (SCD1), an enzyme responsible for the desaturation of saturated fatty acids. Monounsaturated fatty acids generated by SCD1 reduced the surface abundance of the cholesterol efflux transporter ABCA1, which in turn promoted lipid accumulation and induced an inflammatory phagocyte phenotype. Pharmacological inhibition or phagocyte-specific deficiency of Scd1 accelerated remyelination ex vivo and in vivo. These findings identify SCD1 as a novel therapeutic target to promote remyelination.
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ISSN:1540-9538
1540-9538
DOI:10.1084/jem.20191660