Myelin-Derived Lipids Modulate Macrophage Activity by Liver X Receptor Activation

JFJ Bogie, Sarah Schalekamp - Timmermans, AHT Van, A Irrthum, HJM Smeets, JA Gustafsson, KR Steffensen, Maarten Mulder, P Stinissen, N Hellings, JJA Hendriks*

*Corresponding author for this work

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Abstract

Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system in which macrophages and microglia play a central role. Foamy macrophages and microglia, containing degenerated myelin, are abundantly found in active multiple sclerosis lesions. Recent studies have described an altered macrophage phenotype after myelin internalization. However, it is unclear by which mechanisms myelin affects the phenotype of macrophages and how this phenotype can influence lesion progression. Here we demonstrate, by using genome wide gene expression analysis, that myelin-phagocytosing macrophages have an enhanced expression of genes involved in migration, phagocytosis and inflammation. Interestingly, myelin internalization also induced the expression of genes involved in liver-X-receptor signaling and cholesterol efflux. In vitro validation shows that myelin-phagocytosing macrophages indeed have an increased capacity to dispose intracellular cholesterol. In addition, myelin suppresses the secretion of the pro-inflammatory mediator IL-6 by macrophages, which was mediated by activation of liver-X-receptor beta. Our data show that myelin modulates the phenotype of macrophages by nuclear receptor activation, which may subsequently affect lesion progression in demyelinating diseases such as multiple sclerosis.
Original languageUndefined/Unknown
JournalPLoS One (print)
Volume7
Issue number9
DOIs
Publication statusPublished - Sept 2012

Bibliographical note

Funding:
This work was supported by Agentschap voor Innovatie van Wetenschap en Technology (IWT),Fonds Wetenschappelijk Onderzoek (FWO),
transnational University Limburg, Limburg Sterk Merk and Alma-in-Silico (EMR INT4.-1.3.-2008-03/003). This work was partially funded by the Interuniversity
Attraction Poles Programme (IAP P6/25 BIOMAGNET), initiated by the Belgian State, Science Policy Office, by the French Community of Belgium (ARC Biomod),
and by the European Network of Excellence PASCAL2. VAHT is recipient of a Fonds pour la formation a la Recherche dans l’Industrie et dans l’Agriculture (F.R.I.A.)
fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external
funding was received for this study.

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  • EMC COEUR-09

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