005 – Fatty acid desaturation impairs the reparative features of phagocytes in the central nervous system
Elien Grajchen (1#) – Jeroen F.J. Bogie (1#) – Elien Wouters (1) – Aida Garcia Corrales (1) – Tess Dierckx (1) – Mansour Haidar (1) – Jo Mailleux (1) – Pascal Gervois (2) – Esther Wolfs (2) – Jonas Dehairs (3) – Jana Van Broeckhoven (2) – Andrew Bowman (4) – Ivo Lambrichts (2) – Jan-ke Gustafsson (5) – Alan T. Remaley (6) – Monique Mulder (7) – Johannes V. Swinnen (3) – Shane R. Ellis (4) – James M. Ntambi (8) – Noam Zelcer (9) – Jerome J.A. Hendriks (1)
Department of Neuroimmunology and Biochemistry, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium (1) – Department of Morphology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium (2) – Department of Oncology, Laboratory of Lipid Metabolism and Cancer, LKI – Leuven Cancer Institute, KU Leuven – University of Leuven, Leuven, Belgium (3) – M4I, The Maastricht Multimodal Molecular Imaging Institute, Division of Imaging Mass Spectrometry, Maastricht University, Maastricht, The Netherlands (4) – Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, USA; Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden (5) – Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, USA (6) – Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands (7) – Department of Biochemistry, University of Wisconsin-Madison, USA; Department of Nutritional Sciences, University of Wisconsin-Madison, USA (8) – Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (9) – # Equal contribution
Phagocytes are crucially involved in lesion formation and resolution in demyelinating disorders such as multiple sclerosis (MS). To date, it remains poorly understood what drives these cells towards either a disease-promoting or -resolving phenotype. Here, we report that the intracellular myelin load is an important determinant of the phenotypes that phagocytes adopt in demyelinating disorders. While myelin uptake initially suppressed the inflammatory phenotype of phagocytes, sustained intracellular accumulation of myelin countered this protective 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 expression of the cholesterol efflux transporter ABCA1, which in turn promoted the accumulation of inflammatory free cholesterol. Pharmacological inhibition or phagocyte-specific deficiency of SCD1 accelerated remyelination in organotypic brain slices and in the mouse cuprizone model. In conclusion, our findings highlight the importance of FA desaturation in controlling foamy phagocyte function in MS and potentially other neurodegenerative disorders.