title: CD200 restrains macrophage attack on oligodendrocyte precursors via toll-like receptor 4 downregulation.
abstract: There are numerous barriers to white matter repair after central nervous system injury and the underlying mechanisms remain to be fully understood. In this study, we propose the hypothesis that inflammatory macrophages in damaged white matter attack oligodendrocyte precursor cells via toll-like receptor 4 signaling thus interfering with this endogenous progenitor recovery mechanism. Primary cell culture experiments demonstrate that peritoneal macrophages can attack and digest oligodendrocyte precursor cells via toll-like receptor 4 signaling, and this phagocytosis of oligodendrocyte precursor cells can be inhibited by using CD200-Fc to downregulate toll-like receptor 4. In an in vivo model of white matter ischemia induced by endothelin-1, treatment with CD200-Fc suppressed toll-like receptor 4 expression in peripherally circulating macrophages, thus restraining macrophage phagocytosis of oligodendrocyte precursor cells and leading to improved myelination. Taken together, these findings suggest that deleterious macrophage effects may occur after white matter ischemia, whereby macrophages attack oligodendrocyte precursor cells and interfere with endogenous recovery responses. Targeting this pathway with CD200 may offer a novel therapeutic approach to amplify endogenous oligodendrocyte precursor cell-mediated repair of white matter damage in mammalian brain.
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, USA Khayakawa1@mgh.harvard.edu Lo@helix.mgh.harvard.edu.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Hayakawa
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, USA.
authors.forename: Loc-Duyen D
authors.initials: LD
authors.lastname: Pham
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, USA NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Seo
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, USA.
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Miyamoto
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, USA.
authors.forename: Takakuni
authors.initials: T
authors.lastname: Maki
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, USA.
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Terasaki
authors.affiliation: Optics Division, MHG/MIT/HMS Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, USA.
authors.forename: Sava
authors.initials: S
authors.lastname: Sakadžić
authors.affiliation: Optics Division, MHG/MIT/HMS Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, USA.
authors.forename: David
authors.initials: D
authors.lastname: Boas
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: van Leyen
authors.affiliation: Department of Pharmacology and Therapeutics, School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Christian
authors.initials: C
authors.lastname: Waeber
authors.affiliation: NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Arai
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, USA.
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000494:pharmacology*; D002545:Brain Ischemia / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects*; D009836:Oligodendroglia / Q000187:drug effects*; D010587:Phagocytosis / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis* / Q000235:genetics; D066127:White Matter / Q000473:pathology
chemical_list: D015703:Antigens, CD; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D007770:L-Lactate Dehydrogenase; C042739:antigens, CD200
keywords: CD200; macrophage; oligodendrocyte precursors; phagocytosis; white matter injury