title: NG2, a common denominator for neuroinflammation, blood-brain barrier alteration, and oligodendrocyte precursor response in EAE, plays a role in dendritic cell activation.
abstract: In adult CNS, nerve/glial-antigen 2 (NG2) is expressed by oligodendrocyte progenitor cells (OPCs) and is an early marker of pericyte activation in pathological conditions. NG2 could, therefore, play a role in experimental autoimmune encephalomyelitis (EAE), a disease associated with increased blood-brain barrier (BBB) permeability, inflammatory infiltrates, and CNS damage. We induced EAE in NG2 knock-out (NG2KO) mice and used laser confocal microscopy immunofluorescence and morphometry to dissect the effect of NG2 KO on CNS pathology. NG2KO mice developed milder EAE than their wild-type (WT) counterparts, with less intense neuropathology associated with a significant improvement in BBB stability. In contrast to WT mice, OPC numbers did not change in NG2KO mice during EAE. Through FACS and confocal microscopy, we found that NG2 was also expressed by immune cells, including T cells, macrophages, and dendritic cells (DCs). Assessment of recall T cell responses to the encephalitogen by proliferation assays and ELISA showed that, while WT and NG2KO T cells proliferated equally to the encephalitogenic peptide MOG35-55, NG2KO T cells were skewed towards a Th2-type response. Because DCs could be responsible for this effect, we assessed their expression of IL-12 by PCR and intracellular FACS. IL-12-expressing CD11c+ cells were significantly decreased in MOG35-55-primed NG2KO lymph node cells. Importantly, in WT mice, the proportion of IL-12-expressing cells was significantly lower in CD11c+ NG2- cells than in CD11c+ NG2+ cells. To assess the relevance of NG2 at immune system and CNS levels, we induced EAE in bone-marrow chimeric mice, generated with WT recipients of NG2KO bone-marrow cells and vice versa. Regardless of their original phenotype, mice receiving NG2KO bone marrow developed milder EAE than those receiving WT bone marrow. Our data suggest that NG2 plays a role in EAE not only at CNS/BBB level, but also at immune response level, impacting on DC activation and thereby their stimulation of reactive T cells, through controlling IL-12 expression.
authors.affiliation: Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ferrara
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy.
authors.forename: Mariella
authors.initials: M
authors.lastname: Errede
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Girolamo
authors.affiliation: Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Morando
authors.affiliation: Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Ivaldi
authors.affiliation: Department of Neuroscience, IRCCS-Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: Nicolò
authors.initials: N
authors.lastname: Panini
authors.affiliation: Department of Neuroscience, IRCCS-Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
authors.affiliation: Centre for Molecular and Translational Oncology, University of Parma, Parma, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Perris
authors.affiliation: Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Furlan
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Virgintino
authors.affiliation: Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kerlero de Rosbo
authors.affiliation: Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy. auccelli@neurologia.unige.it.|Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy. auccelli@neurologia.unige.it.|IRCCS AOU San Martino - IST, Genoa, Italy. auccelli@neurologia.unige.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Uccelli
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology; D016026:Bone Marrow Transplantation; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
keywords: Blood–brain barrier; DC activation; Experimental autoimmune encephalomyelitis; Nerve/glial-antigen 2; Oligodendrocyte precursor cells; Tight junctions