Journal Article

DZNE-2021-00849

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.

Berghoff, S. A. ; Spieth, L. ; Sun, T.Extern* ; Hosang, L. ; Schlaphoff, L. ; Depp, C. ; Düking, T. ; Winchenbach, J. ; Neuber, J. ; Ewers, D. ; Scholz, P. ; van der Meer, F. ; Cantuti-Castelvetri, L.DZNE* ; Sasmita, A. O. ; Meschkat, M. ; Ruhwedel, T. ; Möbius, W. ; Sankowski, R. ; Prinz, M. ; Huitinga, I. ; Sereda, M. W. ; Odoardi, F. ; Ischebeck, T. ; Simons, M.DZNE* ; Stadelmann-Nessler, C. ; Edgar, J. M. ; Nave, K.-A. ; Saher, G. (Corresponding author)

2021
Nature America New York, NY

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Please use a persistent id in citations: doi:10.1038/s41593-020-00757-6

Abstract: 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.

Keyword(s): Animals (MeSH) ; Cholesterol: metabolism (MeSH) ; Demyelinating Diseases: pathology (MeSH) ; Desmosterol: metabolism (MeSH) ; Encephalomyelitis, Autoimmune, Experimental (MeSH) ; Female (MeSH) ; Gene Expression Profiling (MeSH) ; Humans (MeSH) ; Inflammation: metabolism (MeSH) ; Inflammation: pathology (MeSH) ; Lipid Metabolism (MeSH) ; Liver X Receptors: metabolism (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Microglia: physiology (MeSH) ; Middle Aged (MeSH) ; Multiple Sclerosis (MeSH) ; Oligodendroglia: metabolism (MeSH) ; Phagocytosis (MeSH) ; Squalene: metabolism (MeSH) ; Sterols: biosynthesis (MeSH) ; Liver X Receptors ; Nr1h3 protein, mouse ; Sterols ; Desmosterol ; Squalene ; Cholesterol

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Contributing Institute(s):

1. Molecular Neurobiology (AG Simons)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2021

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 25 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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