title: Myelin-derived lipids modulate macrophage activity by liver X receptor activation.
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 β. 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.
authors.affiliation: Hasselt University/Transnational University Limburg, Biomedical Research Institute, School of Life Sciences, Diepenbeek, Belgium. Jerome.hendriks@uhasselt.be
authors.forename: Jeroen F J
authors.initials: JF
authors.lastname: Bogie
authors.forename: Silke
authors.initials: S
authors.lastname: Timmermans
authors.forename: Vân Anh
authors.initials: VA
authors.lastname: Huynh-Thu
authors.forename: Alexandre
authors.initials: A
authors.lastname: Irrthum
authors.forename: Hubert J M
authors.initials: HJ
authors.lastname: Smeets
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.forename: Knut R
authors.initials: KR
authors.lastname: Steffensen
authors.forename: Monique
authors.initials: M
authors.lastname: Mulder
authors.forename: Piet
authors.initials: P
authors.lastname: Stinissen
authors.forename: Niels
authors.initials: N
authors.lastname: Hellings
authors.forename: Jerome J A
authors.initials: JJ
authors.lastname: Hendriks
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D002784:Cholesterol / Q000276:immunology / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009186:Myelin Sheath / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D018836:Inflammation Mediators; D015850:Interleukin-6; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides