Endogenously regulated Dab2 worsens inflammatory injury in experimental autoimmune encephalomyelitis

Vilija G. Jokubaitis, Melissa M. Gresle, Dennis A. Kemper, William Doherty, Victoria M. Perreau, Tania L. Cipriani, Anna Jonas, Gerry Shaw, Tanja Kuhlmann, Trevor J. Kilpatrick, Helmut Butzkueven

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19 Citations (Scopus)

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.

Original languageEnglish
Article number32
Number of pages14
JournalActa Neuropathologica Communications
Volume1
Issue number1
DOIs
Publication statusPublished - 2013
Externally publishedYes

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