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000155681 0247_ $$2ISSN$$a1546-1726
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000155681 037__ $$aDZNE-2021-00849
000155681 041__ $$aEnglish
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000155681 1001_ $$aBerghoff, Stefan A$$b0
000155681 245__ $$aMicroglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.
000155681 260__ $$aNew York, NY$$bNature America$$c2021
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000155681 520__ $$aThe repair of inflamed, demyelinated lesions as in multiple sclerosis (MS) necessitates the clearance of cholesterol-rich myelin debris by microglia/macrophages and the switch from a pro-inflammatory to an anti-inflammatory lesion environment. Subsequently, oligodendrocytes increase cholesterol levels as a prerequisite for synthesizing new myelin membranes. We hypothesized that lesion resolution is regulated by the fate of cholesterol from damaged myelin and oligodendroglial sterol synthesis. By integrating gene expression profiling, genetics and comprehensive phenotyping, we found that, paradoxically, sterol synthesis in myelin-phagocytosing microglia/macrophages determines the repair of acutely demyelinated lesions. Rather than producing cholesterol, microglia/macrophages synthesized desmosterol, the immediate cholesterol precursor. Desmosterol activated liver X receptor (LXR) signaling to resolve inflammation, creating a permissive environment for oligodendrocyte differentiation. Moreover, LXR target gene products facilitated the efflux of lipid and cholesterol from lipid-laden microglia/macrophages to support remyelination by oligodendrocytes. Consequently, pharmacological stimulation of sterol synthesis boosted the repair of demyelinated lesions, suggesting novel therapeutic strategies for myelin repair in MS.
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000155681 650_7 $$2NLM Chemicals$$aLiver X Receptors
000155681 650_7 $$2NLM Chemicals$$aNr1h3 protein, mouse
000155681 650_7 $$2NLM Chemicals$$aSterols
000155681 650_7 $$0313-04-2$$2NLM Chemicals$$aDesmosterol
000155681 650_7 $$07QWM220FJH$$2NLM Chemicals$$aSqualene
000155681 650_7 $$097C5T2UQ7J$$2NLM Chemicals$$aCholesterol
000155681 650_2 $$2MeSH$$aAnimals
000155681 650_2 $$2MeSH$$aCholesterol: metabolism
000155681 650_2 $$2MeSH$$aDemyelinating Diseases: pathology
000155681 650_2 $$2MeSH$$aDesmosterol: metabolism
000155681 650_2 $$2MeSH$$aEncephalomyelitis, Autoimmune, Experimental
000155681 650_2 $$2MeSH$$aFemale
000155681 650_2 $$2MeSH$$aGene Expression Profiling
000155681 650_2 $$2MeSH$$aHumans
000155681 650_2 $$2MeSH$$aInflammation: metabolism
000155681 650_2 $$2MeSH$$aInflammation: pathology
000155681 650_2 $$2MeSH$$aLipid Metabolism
000155681 650_2 $$2MeSH$$aLiver X Receptors: metabolism
000155681 650_2 $$2MeSH$$aMice
000155681 650_2 $$2MeSH$$aMice, Inbred C57BL
000155681 650_2 $$2MeSH$$aMicroglia: physiology
000155681 650_2 $$2MeSH$$aMiddle Aged
000155681 650_2 $$2MeSH$$aMultiple Sclerosis
000155681 650_2 $$2MeSH$$aOligodendroglia: metabolism
000155681 650_2 $$2MeSH$$aPhagocytosis
000155681 650_2 $$2MeSH$$aSqualene: metabolism
000155681 650_2 $$2MeSH$$aSterols: biosynthesis
000155681 7001_ $$00000-0002-0308-0144$$aSpieth, Lena$$b1
000155681 7001_ $$0P:(DE-2719)2813913$$aSun, Ting$$b2$$udzne
000155681 7001_ $$aHosang, Leon$$b3
000155681 7001_ $$00000-0001-8043-4025$$aSchlaphoff, Lennart$$b4
000155681 7001_ $$00000-0003-2868-6932$$aDepp, Constanze$$b5
000155681 7001_ $$aDüking, Tim$$b6
000155681 7001_ $$aWinchenbach, Jan$$b7
000155681 7001_ $$aNeuber, Jonathan$$b8
000155681 7001_ $$00000-0003-1037-1027$$aEwers, David$$b9
000155681 7001_ $$00000-0003-0761-9175$$aScholz, Patricia$$b10
000155681 7001_ $$avan der Meer, Franziska$$b11
000155681 7001_ $$0P:(DE-2719)2812590$$aCantuti-Castelvetri, Ludovico$$b12$$udzne
000155681 7001_ $$00000-0001-7379-6749$$aSasmita, Andrew O$$b13
000155681 7001_ $$aMeschkat, Martin$$b14
000155681 7001_ $$00000-0002-9535-9395$$aRuhwedel, Torben$$b15
000155681 7001_ $$00000-0002-2902-7165$$aMöbius, Wiebke$$b16
000155681 7001_ $$00000-0001-9215-8021$$aSankowski, Roman$$b17
000155681 7001_ $$00000-0002-0349-1955$$aPrinz, Marco$$b18
000155681 7001_ $$00000-0002-4878-8920$$aHuitinga, Inge$$b19
000155681 7001_ $$aSereda, Michael W$$b20
000155681 7001_ $$aOdoardi, Francesca$$b21
000155681 7001_ $$aIschebeck, Till$$b22
000155681 7001_ $$0P:(DE-2719)2811642$$aSimons, Mikael$$b23$$udzne
000155681 7001_ $$aStadelmann-Nessler, Christine$$b24
000155681 7001_ $$aEdgar, Julia M$$b25
000155681 7001_ $$00000-0001-8724-9666$$aNave, Klaus-Armin$$b26
000155681 7001_ $$00000-0003-3507-9604$$aSaher, Gesine$$b27$$eCorresponding author
000155681 773__ $$0PERI:(DE-600)1494955-6$$a10.1038/s41593-020-00757-6$$gVol. 24, no. 1, p. 47 - 60$$n1$$p47 - 60$$tNature neuroscience$$v24$$x1546-1726$$y2021
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