title: Activated microglia mediate axoglial disruption that contributes to axonal injury in multiple sclerosis.
abstract: The complex manifestations of chronic multiple sclerosis (MS)are due in part to widespread axonal abnormalities that affect lesional and nonlesional areas in the central nervous system. We describe an association between microglial activation and axon/oligodendrocyte pathology at nodal and paranodal domains in normal-appearing white matter (NAWM) of MS cases and in experimental autoimmune encephalomyelitis (EAE). The extent of paranodal axoglial (neurofascin-155(+)/Caspr1(+)) disruption correlated with local microglial inflammation and axonal injury (expression of nonphosphorylated neurofilaments) in MS NAWM. These changes were independent of demyelinating lesions and did not correlate with the density of infiltrating lymphocytes. Similar axoglial alterations were seen in the subcortical white matter of Parkinson disease cases and in preclinical EAE, at a time point when there is microglial activation before the infiltration of immune cells. Disruption of the axoglial unit in adjuvant-immunized animals was reversible and coincided with the resolution of microglial inflammation; paranodal damage and microglial inflammation persisted in chronic EAE. Axoglial integrity could be preserved by the administration of minocycline, which inhibited microglial activation, in actively immunized animals. These data indicate that, in MS NAWM, permanent disruption to axoglial domains in an environment of microglial inflammation is an early indicator of axonal injury that likely affects nerve conduction and may contribute to physiologic dysfunction.
authors.affiliation: Centre for Neuroscience, Division of Experimental Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, London W12 0NN.
authors.forename: Owain W
authors.initials: OW
authors.lastname: Howell
authors.affiliation: Centre for Neuroscience, Division of Experimental Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, London W12 0NN.
authors.forename: Jon L
authors.initials: JL
authors.lastname: Rundle
authors.affiliation: Centre for Neuroscience, Division of Experimental Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, London W12 0NN.
authors.forename: Anurag
authors.initials: A
authors.lastname: Garg
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komada
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brophy
authors.affiliation: Centre for Neuroscience, Division of Experimental Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, London W12 0NN.
authors.forename: Richard
authors.initials: R
authors.lastname: Reynolds
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D001369:Axons / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D017252:CD3 Complex / Q000378:metabolism; D002135:Calcium-Binding Proteins; D020170:Caspase 1 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006023:Glycoproteins; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007211:Indoles; D051663:Kv1.2 Potassium Channel / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins; D017628:Microglia / Q000276:immunology / Q000473:pathology* / Q000502:physiology*; D018613:Microscopy, Confocal; D008875:Middle Aged; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use; D009103:Multiple Sclerosis / Q000473:pathology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010446:Peptide Fragments; D011180:Postmortem Changes; D011901:Ranvier's Nodes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015222:Sodium Channels / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: C112986:AIF1 protein, human; D000900:Anti-Bacterial Agents; D017252:CD3 Complex; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D006684:HLA-DR Antigens; D007211:Indoles; D051663:Kv1.2 Potassium Channel; D008840:Microfilament Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D010446:Peptide Fragments; C100681:SCN8A protein, human; D015222:Sodium Channels; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C445081:myelin oligodendrocyte glycoprotein (35-55); C051774:neurofilament protein H; C007293:DAPI; D052247:Nitric Oxide Synthase Type II; D020170:Caspase 1; D008911:Minocycline