Stearoyl-CoA desaturase-1 impairs the reparative properties of macrophages and microglia in the brain
Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-r...
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| Vydáno v: | The Journal of experimental medicine Ročník 217; číslo 5 |
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| Hlavní autoři: | , , , , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
04.05.2020
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| ISSN: | 1540-9538, 1540-9538 |
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| Abstract | Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-resolving phenotype, while sustained intracellular accumulation of myelin induced a lesion-promoting phenotype. This phenotypic shift was controlled by stearoyl-CoA desaturase-1 (SCD1), an enzyme responsible for the desaturation of saturated fatty acids. Monounsaturated fatty acids generated by SCD1 reduced the surface abundance of the cholesterol efflux transporter ABCA1, which in turn promoted lipid accumulation and induced an inflammatory phagocyte phenotype. Pharmacological inhibition or phagocyte-specific deficiency of Scd1 accelerated remyelination ex vivo and in vivo. These findings identify SCD1 as a novel therapeutic target to promote remyelination. |
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| AbstractList | Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-resolving phenotype, while sustained intracellular accumulation of myelin induced a lesion-promoting phenotype. This phenotypic shift was controlled by stearoyl-CoA desaturase-1 (SCD1), an enzyme responsible for the desaturation of saturated fatty acids. Monounsaturated fatty acids generated by SCD1 reduced the surface abundance of the cholesterol efflux transporter ABCA1, which in turn promoted lipid accumulation and induced an inflammatory phagocyte phenotype. Pharmacological inhibition or phagocyte-specific deficiency of Scd1 accelerated remyelination ex vivo and in vivo. These findings identify SCD1 as a novel therapeutic target to promote remyelination.Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-resolving phenotype, while sustained intracellular accumulation of myelin induced a lesion-promoting phenotype. This phenotypic shift was controlled by stearoyl-CoA desaturase-1 (SCD1), an enzyme responsible for the desaturation of saturated fatty acids. Monounsaturated fatty acids generated by SCD1 reduced the surface abundance of the cholesterol efflux transporter ABCA1, which in turn promoted lipid accumulation and induced an inflammatory phagocyte phenotype. Pharmacological inhibition or phagocyte-specific deficiency of Scd1 accelerated remyelination ex vivo and in vivo. These findings identify SCD1 as a novel therapeutic target to promote remyelination. Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-resolving phenotype, while sustained intracellular accumulation of myelin induced a lesion-promoting phenotype. This phenotypic shift was controlled by stearoyl-CoA desaturase-1 (SCD1), an enzyme responsible for the desaturation of saturated fatty acids. Monounsaturated fatty acids generated by SCD1 reduced the surface abundance of the cholesterol efflux transporter ABCA1, which in turn promoted lipid accumulation and induced an inflammatory phagocyte phenotype. Pharmacological inhibition or phagocyte-specific deficiency of Scd1 accelerated remyelination ex vivo and in vivo. These findings identify SCD1 as a novel therapeutic target to promote remyelination. |
| Author | Lambrichts, Ivo Ellis, Shane R Vanherle, Sam Wolfs, Esther Van Broeckhoven, Jana Haidar, Mansour Mulder, Monique Zelcer, Noam Remaley, Alan T Wouters, Elien Swinnen, Johannes V Corrales, Aida Garcia Grajchen, Elien Mailleux, Jo Dehairs, Jonas Bowman, Andrew P Dierckx, Tess Hendriks, Jerome J A Gustafsson, Jan-Åke Ntambi, James M Bogie, Jeroen F J Gervois, Pascal |
| Author_xml | – sequence: 1 givenname: Jeroen F J surname: Bogie fullname: Bogie, Jeroen F J organization: Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium – sequence: 2 givenname: Elien surname: Grajchen fullname: Grajchen, Elien organization: Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium – sequence: 3 givenname: Elien surname: Wouters fullname: Wouters, Elien organization: Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium – sequence: 4 givenname: Aida Garcia surname: Corrales fullname: Corrales, Aida Garcia organization: Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium – sequence: 5 givenname: Tess surname: Dierckx fullname: Dierckx, Tess organization: Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium – sequence: 6 givenname: Sam surname: Vanherle fullname: Vanherle, Sam organization: Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium – sequence: 7 givenname: Jo surname: Mailleux fullname: Mailleux, Jo organization: Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium – sequence: 8 givenname: Pascal surname: Gervois fullname: Gervois, Pascal organization: Department of Cardio and Organ Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium – sequence: 9 givenname: Esther surname: Wolfs fullname: Wolfs, Esther organization: Department of Cardio and Organ Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium – sequence: 10 givenname: Jonas surname: Dehairs fullname: Dehairs, Jonas organization: Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven Cancer Institute, University of Leuven, Leuven, Belgium – sequence: 11 givenname: Jana surname: Van Broeckhoven fullname: Van Broeckhoven, Jana organization: Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium – sequence: 12 givenname: Andrew P surname: Bowman fullname: Bowman, Andrew P organization: The Maastricht MultiModal Molecular Imaging Institute, Division of Imaging Mass Spectrometry, Maastricht University, Maastricht, Netherlands – sequence: 13 givenname: Ivo surname: Lambrichts fullname: Lambrichts, Ivo organization: Department of Cardio and Organ Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium – sequence: 14 givenname: Jan-Åke surname: Gustafsson fullname: Gustafsson, Jan-Åke organization: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden – sequence: 15 givenname: Alan T surname: Remaley fullname: Remaley, Alan T organization: Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD – sequence: 16 givenname: Monique surname: Mulder fullname: Mulder, Monique organization: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands – sequence: 17 givenname: Johannes V surname: Swinnen fullname: Swinnen, Johannes V organization: Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven Cancer Institute, University of Leuven, Leuven, Belgium – sequence: 18 givenname: Mansour surname: Haidar fullname: Haidar, Mansour organization: Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium – sequence: 19 givenname: Shane R surname: Ellis fullname: Ellis, Shane R organization: The Maastricht MultiModal Molecular Imaging Institute, Division of Imaging Mass Spectrometry, Maastricht University, Maastricht, Netherlands – sequence: 20 givenname: James M surname: Ntambi fullname: Ntambi, James M organization: Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI – sequence: 21 givenname: Noam surname: Zelcer fullname: Zelcer, Noam organization: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands – sequence: 22 givenname: Jerome J A surname: Hendriks fullname: Hendriks, Jerome J A organization: Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium |
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| Title | Stearoyl-CoA desaturase-1 impairs the reparative properties of macrophages and microglia in the brain |
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