title: Endogenously regulated Dab2 worsens inflammatory injury in experimental autoimmune encephalomyelitis.
abstract: BACKGROUND
  Neuroinflammation regulates both disease pathogenesis and repair in multiple sclerosis. In early multiple sclerosis lesion development, neuroinflammation causes demyelination and axonal injury, the likely final common determinant of disability. Here we report the identification of a novel neuroinflammatory mediator, Disabled-2 (Dab2). Dab2 is an intracellular adaptor protein with previously unknown function in the central nervous system.
  
  
  RESULTS
  We report that Dab2 is up-regulated in lesional macrophages/microglia in the spinal cord in murine experimental autoimmune encephalomyelitis, a model of multiple sclerosis. We demonstrate that dab2 expression is positively correlated with experimental autoimmune encephalomyelitis disease severity during the acute disease phase. Furthermore, dab2-deficient mice have a less severe experimental autoimmune encephalomyelitis disease course and suffer less neuroinflammation and less axonal injury than their wild-type littermates. We demonstrate that dab2 expression is strongly associated with the expression of inducible nitric oxide synthase. We further demonstrate that Dab2 is expressed at the protein level by macrophages in early acute human multiple sclerosis lesions and that this correlates with axonal injury.
  
  
  CONCLUSIONS
  Together, these results suggest that endogenous Dab2 exacerbates central nervous system inflammation, potentially acting to up-regulate reactive oxygen species expression in macrophages and microglia, and that it is of potential pathogenic relevance in Multiple Sclerosis.
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia. vilija.jokubaitis@unimelb.edu.au.
authors.forename: Vilija G
authors.initials: VG
authors.lastname: Jokubaitis
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Gresle
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Kemper
authors.forename: William
authors.initials: W
authors.lastname: Doherty
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Perreau
authors.forename: Tania L
authors.initials: TL
authors.lastname: Cipriani
authors.forename: Anna
authors.initials: A
authors.lastname: Jonas
authors.forename: Gerry
authors.initials: G
authors.lastname: Shaw
authors.forename: Tanja
authors.initials: T
authors.lastname: Kuhlmann
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Kilpatrick
authors.forename: Helmut
authors.initials: H
authors.lastname: Butzkueven
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D005260:Female; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism; D015213:Neuroimmunomodulation / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000276:immunology*; D013601:T-Lymphocytes / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; C478773:Dab2 protein, mouse; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D025521:Tumor Suppressor Proteins; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse