TY - JOUR TI - Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis 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 T2 - Nature Neuroscience 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. DA - 2020/12/21/ PY - 2020 DO - 10.1038/s41593-020-00757-6 DP - www.nature.com SP - 1 EP - 14 LA - en SN - 1546-1726 UR - https://www.nature.com/articles/s41593-020-00757-6 Y2 - 2020/12/21/18:00:11 ER -