title: Transgenic inhibition of astroglial NF-κB protects from optic nerve damage and retinal ganglion cell loss in experimental optic neuritis.
abstract: BACKGROUND
  Optic neuritis is an acute, demyelinating neuropathy of the optic nerve often representing the first appreciable symptom of multiple sclerosis. Wallerian degeneration of irreversibly damaged optic nerve axons leads to death of retinal ganglion cells, which is the cause of permanent visual impairment. Although the specific mechanisms responsible for triggering these events are unknown, it has been suggested that a key pathological factor is the activation of immune-inflammatory processes secondary to leukocyte infiltration. However, to date, there is no conclusive evidence to support such a causal role for infiltrating peripheral immune cells in the etiopathology of optic neuritis.
  
  
  METHODS
  To dissect the contribution of the peripheral immune-inflammatory response versus the CNS-specific inflammatory response in the development of optic neuritis, we analyzed optic nerve and retinal ganglion cells pathology in wild-type and GFAP-IκBα-dn transgenic mice, where NF-κB is selectively inactivated in astrocytes, following induction of EAE.
  
  
  RESULTS
  We found that, in wild-type mice, axonal demyelination in the optic nerve occurred as early as 8 days post induction of EAE, prior to the earliest signs of leukocyte infiltration (20 days post induction). On the contrary, GFAP-IκBα-dn mice were significantly protected and showed a nearly complete prevention of axonal demyelination, as well as a drastic attenuation in retinal ganglion cell death. This correlated with a decrease in the expression of pro-inflammatory cytokines, chemokines, adhesion molecules, as well as a prevention of NAD(P)H oxidase subunit upregulation.
  
  
  CONCLUSIONS
  Our results provide evidence that astrocytes, not infiltrating immune cells, play a key role in the development of optic neuritis and that astrocyte-mediated neurotoxicity is dependent on activation of a transcriptional program regulated by NF-κB. Hence, interventions targeting the NF-κB transcription factor in astroglia may be of therapeutic value in the treatment of optic neuritis associated with multiple sclerosis.
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, FL 33136, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Brambilla
authors.forename: Galina
authors.initials: G
authors.lastname: Dvoriantchikova
authors.forename: David
authors.initials: D
authors.lastname: Barakat
authors.forename: Dmitry
authors.initials: D
authors.lastname: Ivanov
authors.forename: John R
authors.initials: JR
authors.lastname: Bethea
authors.forename: Valery I
authors.initials: VI
authors.lastname: Shestopalov
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000473:pathology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology; D009901:Optic Nerve Diseases / Q000209:etiology / Q000517:prevention & control*; D018384:Oxidative Stress / Q000502:physiology; D010446:Peptide Fragments / Q000633:toxicity; D010655:Phenylenediamines / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology*
chemical_list: D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D016328:NF-kappa B; D010446:Peptide Fragments; D010655:Phenylenediamines; C445081:myelin oligodendrocyte glycoprotein (35-55); C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D010751:Phosphopyruvate Hydratase; C029728:4-phenylenediamine