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Article The ApoA-I mimetic peptide 5A enhances remyelination by promoting clearance and degradation of myelin debris Graphical abstract Highlights d ApoA-I mimetic peptide 5A enhances remyelination in a phagocyte-dependent manner d In addition to promoting lipid efflux, peptide 5A enhances clearance of myelin debris d Peptide 5A drives clearance of myelin debris via the fatty acid translocase CD36 We thank M.P. Tulleners for excellent technical assistance. The work was financially supported by the Research Foundation of Flanders (FWO Vlaanderen; 1S15519N, G099618FWO, and 12J9119N) and the Interreg V-A EMR program (EURLIPIDS, EMR23). The funding agencies had no role in the design, analysis, or writing of the article.

The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity. To date, however, the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood. Here, we report that stearoyl-CoA desaturase-1 (SCD1), an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors, acts as an endogenous brake on regulatory T-cell (Treg) differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner. Guided by RNA sequencing and lipidomics analysis, we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase (ATGL). ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma. Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity, with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS. The work has been supported by the Flemish Fund for Scientific Research (FWO Vlaanderen; 12J9116N, 12JG119N, 12U7718N, 1S15519N, and G099618N), the Belgian Charcot Foundation (FCS-2016-EG7, R-8676, and R-6832), the Interreg V‐A EMR program (EURLIPIDS, EMR23), and the special research fund UHasselt (BOF). JMN is supported by a National Institutes of Health Grant (R01 DK062388). MK was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (640116) and by a SALK grant from the government of Flanders and by an Odysseus grant of the Research Foundation Flanders, Belgium (FWO). We thank MP Tulleners for excellent technical assistance. We would also like to thank other members of the Biomedical Research Institute (Hasselt University) for providing feedback and suggestions during the preparation of the manuscript.

Lysoplasmalogens are a class of vinyl ether bioactive lipids that have a central role in plasmalogen metabolism and membrane fluidity. The liver X re-ceptor (LXR) transcription factors are important de-terminants of cellular lipid homeostasis owing to their ability to regulate cholesterol and fatty acid meta-bolism. However, their role in governing the compo-sition of lipid species such as lysoplasmalogens in cellular membranes is less well studied. Here, we mapped the lipidome of bone marrow-derived mac-rophages (BMDMs) following LXR activation. We found a marked reduction in the levels of lyso-plasmalogen species in the absence of changes in the levels of plasmalogens themselves. Transcriptional profiling of LXR-activated macrophages identified the gene encoding transmembrane protein 86a (TMEM86a), an integral endoplasmic reticulum pro-tein, as a previously uncharacterized sterol-regulated gene. We demonstrate that TMEM86a is a direct transcriptional target of LXR in macrophages and microglia and that it is highly expressed in TREM2 thorn / lipid-associated macrophages in human atherosclerotic plaques, where its expression positively correlates with other LXR-regulated genes. We further show that both murine and human TMEM86a display active lysoplasmalogenase activity that can be abrogated by inactivating mutations in the predicted catalytic site. Consequently, we demonstrate that overexpression of Tmem86a in BMDM markedly reduces lysoplasmalogen abundance and membrane fluidity, while reciprocally, silencing of Tmem86a increases basal lysoplasmalogen levels and abrogates the LXR-dependent reduction of this lipid species. Collectively, our findings implicate TMEM86a as a sterol-regulated lysoplasma-logenase in macrophages that contributes to sterol -dependent membrane remodeling. N. Z. is an Established Investigator of the Dutch Heart Foundation (2013T111) and is supported by an ERC Consolidator grant (617376) and by a Vici grant from the Netherlands Organization for Scientific Research (NWO; 016.176.643).

The progressive nature of demyelinating diseases lies in the inability of the central nervous system (CNS) to induce proper remyelination. Recently, we and others demonstrated that a dysregulated innate immune response partially underlies failure of CNS remyelination. Extensive accumulation of myelin-derived lipids and an inability to process these lipids was found to induce a disease-promoting phagocyte phenotype. Hence, restoring the ability of these phagocytes to metabolize and efflux myelin-derived lipids represents a promising strategy to promote remyelination. Here, we show that ApoA-I mimetic peptide 5A, a molecule well known to promote activity of the lipid efflux transporter ABCA1, markedly enhances remyelination. Mechanistically, we find that the repair-inducing properties of 5A are attributable to increased clearance and metabolism of remyelination-inhibiting myelin debris via the fatty acid translocase protein CD36, which is transcriptionally controlled by the ABCA1-JAK2-STAT3 signaling pathway. Altogether, our findings indi-cate that 5A promotes remyelination by stimulating clearance and degradation of myelin debris. We thank M.P. Tulleners for excellent technical assistance. The work was financially supported by the Research Foundation of Flanders (FWO Vlaanderen; 1S15519N, G099618FWO, and 12J9119N) and the Interreg V-A EMR program (EURLIPIDS, EMR23). The funding agencies had no role in the design, analysis, or writing of the article.