title: Myelin alters the inflammatory phenotype of macrophages by activating PPARs.
abstract: BACKGROUND
  Foamy macrophages, containing myelin degradation products, are abundantly found in active multiple sclerosis (MS) lesions. Recent studies have described an altered phenotype of macrophages after myelin internalization. However, mechanisms by which myelin affects the phenotype of macrophages and how this phenotype influences lesion progression remain unclear.
  
  
  RESULTS
  We demonstrate that myelin as well as phosphatidylserine (PS), a phospholipid found in myelin, reduce nitric oxide production by macrophages through activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ). Furthermore, uptake of PS by macrophages, after intravenous injection of PS-containing liposomes (PSLs), suppresses the production of inflammatory mediators and ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The protective effect of PSLs in EAE animals is associated with a reduced immune cell infiltration into the central nervous system and decreased splenic cognate antigen specific proliferation. Interestingly, PPARβ/δ is activated in foamy macrophages in active MS lesions, indicating that myelin also activates PPARβ/δ in macrophages in the human brain.
  
  
  CONCLUSIONS
  Our data show that myelin modulates the phenotype of macrophages by PPAR activation, which may subsequently dampen MS lesion progression. Moreover, our results suggest that myelin-derived PS mediates PPARβ/δ activation in macrophages after myelin uptake. The immunoregulatory impact of naturally-occurring myelin lipids may hold promise for future MS therapeutics.
authors.affiliation: Biomedical Research Institute, School of Life Sciences, Hasselt University / Transnational University Limburg, Diepenbeek, Belgium. Jerome.Hendriks@uhasselt.be.
authors.forename: Jeroen F J
authors.initials: JF
authors.lastname: Bogie
authors.forename: Winde
authors.initials: W
authors.lastname: Jorissen
authors.forename: Jo
authors.initials: J
authors.lastname: Mailleux
authors.forename: Philip G
authors.initials: PG
authors.lastname: Nijland
authors.forename: Noam
authors.initials: N
authors.lastname: Zelcer
authors.forename: Tim
authors.initials: T
authors.lastname: Vanmierlo
authors.forename: Jack
authors.initials: J
authors.lastname: Van Horssen
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: D000328:Adult; D000368:Aged; D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D009186:Myelin Sheath / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism*; D048068:PPAR-beta / Q000378:metabolism*; D010718:Phosphatidylserines / Q000008:administration & dosage / Q000378:metabolism; D051381:Rats; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000502:physiology
chemical_list: D047494:PPAR delta; D048068:PPAR-beta; D010718:Phosphatidylserines; D009569:Nitric Oxide