TY  - JOUR
AU  - Berghoff, Stefan A
AU  - Spieth, Lena
AU  - Sun, Ting
AU  - Hosang, Leon
AU  - Schlaphoff, Lennart
AU  - Depp, Constanze
AU  - Düking, Tim
AU  - Winchenbach, Jan
AU  - Neuber, Jonathan
AU  - Ewers, David
AU  - Scholz, Patricia
AU  - van der Meer, Franziska
AU  - Cantuti-Castelvetri, Ludovico
AU  - Sasmita, Andrew O
AU  - Meschkat, Martin
AU  - Ruhwedel, Torben
AU  - Möbius, Wiebke
AU  - Sankowski, Roman
AU  - Prinz, Marco
AU  - Huitinga, Inge
AU  - Sereda, Michael W
AU  - Odoardi, Francesca
AU  - Ischebeck, Till
AU  - Simons, Mikael
AU  - Stadelmann-Nessler, Christine
AU  - Edgar, Julia M
AU  - Nave, Klaus-Armin
AU  - Saher, Gesine
TI  - Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.
JO  - Nature neuroscience
VL  - 24
IS  - 1
SN  - 1546-1726
CY  - New York, NY
PB  - Nature America
M1  - DZNE-2021-00849
SP  - 47 - 60
PY  - 2021
AB  - 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.
KW  - Animals
KW  - Cholesterol: metabolism
KW  - Demyelinating Diseases: pathology
KW  - Desmosterol: metabolism
KW  - Encephalomyelitis, Autoimmune, Experimental
KW  - Female
KW  - Gene Expression Profiling
KW  - Humans
KW  - Inflammation: metabolism
KW  - Inflammation: pathology
KW  - Lipid Metabolism
KW  - Liver X Receptors: metabolism
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Microglia: physiology
KW  - Middle Aged
KW  - Multiple Sclerosis
KW  - Oligodendroglia: metabolism
KW  - Phagocytosis
KW  - Squalene: metabolism
KW  - Sterols: biosynthesis
KW  - Liver X Receptors (NLM Chemicals)
KW  - Nr1h3 protein, mouse (NLM Chemicals)
KW  - Sterols (NLM Chemicals)
KW  - Desmosterol (NLM Chemicals)
KW  - Squalene (NLM Chemicals)
KW  - Cholesterol (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:33349711
C2  - pmc:PMC7116742
DO  - DOI:10.1038/s41593-020-00757-6
UR  - https://pub.dzne.de/record/155681
ER  -