title: CNS myelin induces regulatory functions of DC-SIGN-expressing, antigen-presenting cells via cognate interaction with MOG.
abstract: Myelin oligodendrocyte glycoprotein (MOG), a constituent of central nervous system myelin, is an important autoantigen in the neuroinflammatory disease multiple sclerosis (MS). However, its function remains unknown. Here, we show that, in healthy human myelin, MOG is decorated with fucosylated N-glycans that support recognition by the C-type lectin receptor (CLR) DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) on microglia and DCs. The interaction of MOG with DC-SIGN in the context of simultaneous TLR4 activation resulted in enhanced IL-10 secretion and decreased T cell proliferation in a DC-SIGN-, glycosylation-, and Raf1-dependent manner. Exposure of oligodendrocytes to proinflammatory factors resulted in the down-regulation of fucosyltransferase expression, reflected by altered glycosylation at the MS lesion site. Indeed, removal of fucose on myelin reduced DC-SIGN-dependent homeostatic control, and resulted in inflammasome activation, increased T cell proliferation, and differentiation toward a Th17-prone phenotype. These data demonstrate a new role for myelin glycosylation in the control of immune homeostasis in the healthy human brain through the MOG-DC-SIGN homeostatic regulatory axis, which is comprised by inflammatory insults that affect glycosylation. This phenomenon should be considered as a basis to restore immune tolerance in MS.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081HV Amsterdam, Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: García-Vallejo
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081HV Amsterdam, Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: Ilarregui
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081HV Amsterdam, Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Kalay
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081HV Amsterdam, Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Chamorro
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081HV Amsterdam, Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Koning
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081HV Amsterdam, Netherlands.
authors.forename: W W
authors.initials: WW
authors.lastname: Unger
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081HV Amsterdam, Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Ambrosini
authors.affiliation: Division of Cell Biology, Dutch Cancer Institute, 1066X Amsterdam, Netherlands.
authors.forename: V
authors.initials: V
authors.lastname: Montserrat
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081HV Amsterdam, Netherlands.
authors.forename: R J
authors.initials: RJ
authors.lastname: Fernandes
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081HV Amsterdam, Netherlands.
authors.forename: S C M
authors.initials: SC
authors.lastname: Bruijns
authors.affiliation: Department of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam; and Department of Pathology, VU University Amsterdam, VU University Medical Center, 1081HV Amsterdam, Netherlands.
authors.forename: J R T
authors.initials: JR
authors.lastname: van Weering
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081HV Amsterdam, Netherlands.
authors.forename: N J
authors.initials: NJ
authors.lastname: Paauw
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081HV Amsterdam, Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: O'Toole
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081HV Amsterdam, Netherlands Department of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam; and Department of Pathology, VU University Amsterdam, VU University Medical Center, 1081HV Amsterdam, Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: van Horssen
authors.affiliation: Department of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam; and Department of Pathology, VU University Amsterdam, VU University Medical Center, 1081HV Amsterdam, Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: van der Valk
authors.affiliation: Department of Oral Biochemistry, Academic Centre for Dentistry Amsterdam, University of Amsterdam, VU University, 1081LA Amsterdam, Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Nazmi
authors.affiliation: Department of Oral Biochemistry, Academic Centre for Dentistry Amsterdam, University of Amsterdam, VU University, 1081LA Amsterdam, Netherlands.
authors.forename: J G M
authors.initials: JG
authors.lastname: Bolscher
authors.affiliation: Alternatives Unit and Dept. Immunobiology, Biomedical Primate Research Centre, 2280 GH Rijswijk, Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Bajramovic
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081HV Amsterdam, Netherlands.
authors.forename: C D
authors.initials: CD
authors.lastname: Dijkstra
authors.affiliation: Alternatives Unit and Dept. Immunobiology, Biomedical Primate Research Centre, 2280 GH Rijswijk, Netherlands Department Neuroscience, University Medical Center, University of Groningen, 9713GZ Groningen, Netherlands.
authors.forename: B A
authors.initials: BA
authors.lastname: 't Hart
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081HV Amsterdam, Netherlands y.vankooyk@vumc.nl.
authors.forename: Y
authors.initials: Y
authors.lastname: van Kooyk
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000276:immunology*; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology*; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology*; D008297:Male; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000235:genetics / Q000276:immunology*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D058847:Inflammasomes; D018836:Inflammation Mediators; D016753:Interleukin-10; D037181:Lectins, C-Type; D063308:Myelin-Oligodendrocyte Glycoprotein; D019908:Proto-Oncogene Proteins c-raf; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C508609:IL10 protein, human; C571326:MOG protein, human; C495345:TLR4 protein, human