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Title: | Fatty acid elongation by ELOVL6 hampers remyelination by promoting inflammatory foam cell formation during demyelination | Authors: | GARCIA CORRALES, Aida VERBERK, Sanne HAIDAR, Mansour GRAJCHEN, Elien Dehairs, Jonas VANHERLE, Sam LOIX, Melanie WEYTJENS, Tine GERVOIS, Pascal Matsuzaka, Takashi LAMBRICHTS, Ivo Swinnen, Johannes V. BOGIE, Jeroen HENDRIKS, Jerome |
Issue Date: | 2023 | Publisher: | NATL ACAD SCIENCES | Source: | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 120 (37) (Art N° e2301030120) | Abstract: | A hallmark of multiple sclerosis (MS) is the formation of multiple focal demyelinating lesions within the central nervous system (CNS). These lesions mainly consist of phagocytes that play a key role in lesion progression and remyelination, and therefore represent a promising therapeutic target in MS. We recently showed that unsaturated fatty acids produced by stearoyl-CoA desaturase-1 induce inflammatory foam cell formation during demyelination. These fatty acids are elongated by the "elongation of very long chain fatty acids" proteins (ELOVLs), generating a series of functionally distinct lipids. Here, we show that the expression and activity of ELOVLs are altered in myelin-induced foam cells. Especially ELOVL6, an enzyme responsible for converting saturated and mono-unsaturated C16 fatty acids into C18 species, was found to be up-regulated in myelin phagocytosing phagocytes in vitro and in MS lesions. Depletion of Elovl6 induced a repair-promoting phagocyte phenotype through activation of the S1P/PPAR. pathway. Elovl6-deficient foamy macrophages showed enhanced ABCA1-mediated lipid efflux, increased production of neurotrophic factors, and reduced expression of inflammatory mediators. Moreover, our data show that ELOVL6 hampers CNS repair, as Elovl6 deficiency prevented demyelination and boosted remyelination in organotypic brain slice cultures and the mouse cuprizone model. These findings indicate that targeting ELOVL6 activity may be an effective strategy to stimulate CNS repair in MS and other neurodegenerative diseases. | Notes: | Hendriks, JJA (corresponding author), Hasselt Univ, Biomed Res Inst, Dept Immunol & Infect, B-3590 Diepenbeek, Belgium. jerome.hendriks@uhasselt.be |
Keywords: | multiple sclerosis;fatty acid metabolism;remyelination;macrophage | Document URI: | http://hdl.handle.net/1942/42213 | ISSN: | 0027-8424 | e-ISSN: | 1091-6490 | DOI: | 10.1073/pnas.2301030120 | ISI #: | 001119304600001 | Rights: | 2023 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial- NoDerivatives License 4.0 (CC BY-NC- ND). | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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