دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.
المؤلفون: Berghoff SA; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany., Spieth L; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany., Sun T; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.; Institute for Medical Systems Biology, Center for Molecular Neurobiology Hamburg, Hamburg, Germany., Hosang L; Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Center Göttingen, Göttingen, Germany., Schlaphoff L; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany., Depp C; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany., Düking T; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany., Winchenbach J; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany., Neuber J; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany., Ewers D; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.; Department of Clinical Neurophysiology, University Medical Centre Göttingen, Göttingen, Germany.; Department of Neurology, University Medical Centre, Göttingen, Germany., Scholz P; Department of Plant Biochemistry, Albrecht-von-Haller-Institute for Plant Sciences and Göttingen Center for Molecular Biosciences (GZMB), University of Göttingen, Göttingen, Germany., van der Meer F; Institute for Neuropathology, University Medical Centre Göttingen, Göttingen, Germany., Cantuti-Castelvetri L; Institute of Neuronal Cell Biology, Technical University Munich, German Center for Neurodegenerative Diseases, Munich Cluster of Systems Neurology (SyNergy), Munich, Germany., Sasmita AO; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany., Meschkat M; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany., Ruhwedel T; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany., Möbius W; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany., Sankowski R; Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany., Prinz M; Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.; Center for Basics in NeuroModulation (NeuroModul Basics), Faculty of Medicine, University of Freiburg, Freiburg, Germany., Huitinga I; Neuroimmunology Research Group, Netherlands Institute for Neuroscience, an institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands., Sereda MW; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.; Department of Clinical Neurophysiology, University Medical Centre Göttingen, Göttingen, Germany.; Department of Neurology, University Medical Centre, Göttingen, Germany., Odoardi F; Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Center Göttingen, Göttingen, Germany., Ischebeck T; Department of Plant Biochemistry, Albrecht-von-Haller-Institute for Plant Sciences and Göttingen Center for Molecular Biosciences (GZMB), University of Göttingen, Göttingen, Germany.; Service Unit for Metabolomics and Lipidomics, Göttingen Center for Molecular Biosciences (GZMB), University of Göttingen, Göttingen, Germany., Simons M; Institute of Neuronal Cell Biology, Technical University Munich, German Center for Neurodegenerative Diseases, Munich Cluster of Systems Neurology (SyNergy), Munich, Germany., Stadelmann-Nessler C; Institute for Neuropathology, University Medical Centre Göttingen, Göttingen, Germany., Edgar JM; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.; Applied Neurobiology Group, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Nave KA; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany. nave@em.mpg.de., Saher G; Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany. saher@em.mpg.de.
المصدر: Nature neuroscience [Nat Neurosci] 2021 Jan; Vol. 24 (1), pp. 47-60. Date of Electronic Publication: 2020 Dec 21.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 9809671 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1726 (Electronic) Linking ISSN: 10976256 NLM ISO Abbreviation: Nat Neurosci Subsets: MEDLINE
أسماء مطبوعة: Publication: <2002->: New York, NY : Nature Publishing Group
Original Publication: New York, NY : Nature America Inc., c1998-
مواضيع طبية MeSH: Demyelinating Diseases/*pathology , Microglia/*physiology , Sterols/*biosynthesis, Animals ; Cholesterol/metabolism ; Desmosterol/metabolism ; Encephalomyelitis, Autoimmune, Experimental ; Female ; Gene Expression Profiling ; Humans ; Inflammation/metabolism ; Inflammation/pathology ; Lipid Metabolism ; Liver X Receptors/metabolism ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Multiple Sclerosis ; Oligodendroglia/metabolism ; Phagocytosis ; Squalene/metabolism
مستخلص: 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.
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معلومات مُعتمدة: 204034 International ERC_ European Research Council; 269020 International ERC_ European Research Council; 38.0 United Kingdom MSS_ Multiple Sclerosis Society; NC/L000423/1 United Kingdom NC3RS_ National Centre for the Replacement, Refinement and Reduction of Animals in Research
المشرفين على المادة: 0 (Liver X Receptors)
0 (Nr1h3 protein, mouse)
0 (Sterols)
313-04-2 (Desmosterol)
7QWM220FJH (Squalene)
97C5T2UQ7J (Cholesterol)
تواريخ الأحداث: Date Created: 20201222 Date Completed: 20210308 Latest Revision: 20240329
رمز التحديث: 20240329
مُعرف محوري في PubMed: PMC7116742
DOI: 10.1038/s41593-020-00757-6
PMID: 33349711
قاعدة البيانات: MEDLINE
الوصف
تدمد:1546-1726
DOI:10.1038/s41593-020-00757-6