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

Stefan A. Berghoff; Lena Spieth; Ting Sun; Leon Hosang; Lennart Schlaphoff; Constanze Depp; Tim Duking; Jan Winchenbach; Jonathan Neuber; David Ewers; Patricia Scholz; Franziska van der Meer; Ludovico Cantuti-Castelvetri; Andrew O. Sasmita; Martin Meschkat; Torben Ruhwedel; Wiebke Mobius; Roman Sankowski; Marco Prinz; I. Huitinga; Michael W. Sereda; Francesca Odoardi; Till Ischebeck; Mikael Simons; Christine Stadelman-Nessler; Julia M. Edgar; Klaus-Armin Nave; Gesine Saher

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

Stefan A. Berghoff, Lena Spieth, Ting Sun, Leon Hosang, Lennart Schlaphoff, Constanze Depp, Tim Duking, Jan Winchenbach, Jonathan Neuber, David Ewers, Patricia Scholz, Franziska van der Meer, Ludovico Cantuti-Castelvetri, Andrew O. Sasmita, Martin Meschkat, Torben Ruhwedel, Wiebke Mobius, Roman Sankowski, Marco Prinz, I. HuitingaMichael W. Sereda, Francesca Odoardi, Till Ischebeck, Mikael Simons, Christine Stadelman-Nessler, Julia M. Edgar, Klaus-Armin Nave, Gesine Saher

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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.

Originele taal-2	Engels
Pagina's (van-tot)	47-60
Tijdschrift	Nature Neuroscience
Volume	24
Status	Gepubliceerd - 04 jan 2021

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https://www.nature.com/articles/s41593-020-00757-6

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Berghoff, S. A., Spieth, L., Sun, T., Hosang, L., Schlaphoff, L., Depp, C., Duking, T., Winchenbach, J., Neuber, J., Ewers, D., Scholz, P., van der Meer, F., Cantuti-Castelvetri, L., Sasmita, A. O., Meschkat, M., Ruhwedel, T., Mobius, W., Sankowski, R., Prinz, M., ... Saher, G. (2021). Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis. Nature Neuroscience, 24, 47-60. https://www.nature.com/articles/s41593-020-00757-6

Berghoff, Stefan A. ; Spieth, Lena ; Sun, Ting ; Hosang, Leon ; Schlaphoff, Lennart ; Depp, Constanze ; Duking, Tim ; Winchenbach, Jan ; Neuber, Jonathan ; Ewers, David ; Scholz, Patricia ; van der Meer, Franziska ; Cantuti-Castelvetri, Ludovico ; Sasmita, Andrew O. ; Meschkat, Martin ; Ruhwedel, Torben ; Mobius, Wiebke ; Sankowski, Roman ; Prinz, Marco ; Huitinga, I. ; Sereda, Michael W. ; Odoardi, Francesca ; Ischebeck, Till ; Simons, Mikael ; Stadelman-Nessler, Christine ; Edgar, Julia M. ; Nave, Klaus-Armin ; Saher, Gesine. / Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis. In: Nature Neuroscience. 2021 ; Vol. 24. blz. 47-60.

@article{998399252317482f84d335ccaca51264,

title = "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.",

author = "Berghoff, {Stefan A.} and Lena Spieth and Ting Sun and Leon Hosang and Lennart Schlaphoff and Constanze Depp and Tim Duking and Jan Winchenbach and Jonathan Neuber and David Ewers and Patricia Scholz and {van der Meer}, Franziska and Ludovico Cantuti-Castelvetri and Sasmita, {Andrew O.} and Martin Meschkat and Torben Ruhwedel and Wiebke Mobius and Roman Sankowski and Marco Prinz and I. Huitinga and Sereda, {Michael W.} and Francesca Odoardi and Till Ischebeck and Mikael Simons and Christine Stadelman-Nessler and Edgar, {Julia M.} and Klaus-Armin Nave and Gesine Saher",

year = "2021",

month = jan,

day = "4",

language = "English",

volume = "24",

pages = "47--60",

journal = "Nature Neuroscience",

issn = "1097-6256",

publisher = "Nature Publishing Group",

}

Berghoff, SA, Spieth, L, Sun, T, Hosang, L, Schlaphoff, L, Depp, C, Duking, T, Winchenbach, J, Neuber, J, Ewers, D, Scholz, P, van der Meer, F, Cantuti-Castelvetri, L, Sasmita, AO, Meschkat, M, Ruhwedel, T, Mobius, W, Sankowski, R, Prinz, M, Huitinga, I, Sereda, MW, Odoardi, F, Ischebeck, T, Simons, M, Stadelman-Nessler, C, Edgar, JM, Nave, K-A & Saher, G 2021, 'Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.', Nature Neuroscience, vol. 24, blz. 47-60. <https://www.nature.com/articles/s41593-020-00757-6>

Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis. / Berghoff, Stefan A.; Spieth, Lena; Sun, Ting; Hosang, Leon; Schlaphoff, Lennart; Depp, Constanze; Duking, Tim; Winchenbach, Jan; Neuber, Jonathan; Ewers, David; Scholz, Patricia; van der Meer, Franziska; Cantuti-Castelvetri, Ludovico; Sasmita, Andrew O.; Meschkat, Martin; Ruhwedel, Torben; Mobius, Wiebke; Sankowski, Roman; Prinz, Marco; Huitinga, I.; Sereda, Michael W.; Odoardi, Francesca; Ischebeck, Till; Simons, Mikael; Stadelman-Nessler, Christine; Edgar, Julia M.; Nave, Klaus-Armin; Saher, Gesine.

In: Nature Neuroscience, Vol. 24, 04.01.2021, blz. 47-60.

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

TY - JOUR

T1 - 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 - Duking, 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 - Mobius, Wiebke

AU - Sankowski, Roman

AU - Prinz, Marco

AU - Huitinga, I.

AU - Sereda, Michael W.

AU - Odoardi, Francesca

AU - Ischebeck, Till

AU - Simons, Mikael

AU - Stadelman-Nessler, Christine

AU - Edgar, Julia M.

AU - Nave, Klaus-Armin

AU - Saher, Gesine

PY - 2021/1/4

Y1 - 2021/1/4

N2 - 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.

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.

M3 - Article

VL - 24

SP - 47

EP - 60

JO - Nature Neuroscience

JF - Nature Neuroscience

SN - 1097-6256

ER -

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

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