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

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.

• Authors: Stefan A Berghoff, Lena Spieth, Ting Sun, Leon Hosang, Lennart Schlaphoff, Constanze Depp, Tim Düking, Jan Winchenbach, Jonathan Neuber, David Ewers, Patricia Scholz, Franziska van der Meer, Ludovico Cantuti-Castelvetri, Andrew O Sasmita, Martin Meschkat, Torben Ruhwedel, Wiebke Möbius, Roman Sankowski, Marco Prinz, Inge Huitinga, Michael W Sereda, Francesca Odoardi, Till Ischebeck, Mikael Simons, Christine Stadelmann-Nessler, Julia M Edgar, Klaus-Armin Nave, Gesine Saher
• Journal: Nature neuroscience (Nat Neurosci) Vol. 24 Issue 1 Pg. 47-60 (01 2021) ISSN: 1546-1726 [Electronic] United States
• PMID: 33349711 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Liver X Receptors
• Nr1h3 protein, mouse
• Sterols
• Desmosterol
• Squalene
• Cholesterol

Topics

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