Endogenously regulated Dab2 worsens inflammatory injury in experimental autoimmune encephalomyelitis

Abstract

BackgroundNeuroinflammation 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.ResultsWe 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.ConclusionsTogether, 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.

Transient activation of an adaptor protein, disabled-2, in rat spinal cord injury

“…They also found that Dab2-deficient mice had less severe EAE than wild-type littermates (Jokubaitis et al, 2013). Dab-2 is an important molecule in cells and follows multiple cascades related to cell activation, but its role should be studied further.…”

“…Recently, Jokubaitis et al (2013) reported an association between Dab-2 and nitric oxide generation in an EAE model, with Dab-2 detected concomitantly with inducible nitric oxide synthase (iNOS) in EAE and multiple sclerosis brain lesions. They also found that Dab2-deficient mice had less severe EAE than wild-type littermates (Jokubaitis et al, 2013).…”

Disabled homolog 2 controls macrophage phenotypic polarization and adipose tissue inflammation

“…IFN-γ, which promotes M1 phenotypic polarization in macrophages, induces the expression of IFN consensus sequence-binding protein (ICSBP, also known as IRF8), which in turn transcriptionally represses Dab2 (40). Upregulation of DAB2 was observed in spinal cord lesions in murine experimental autoimmune encephalomyelitis (41).…”

Matrine Treatment Blocks NogoA-Induced Neural Inhibitory Signaling Pathway in Ongoing Experimental Autoimmune Encephalomyelitis

“…MAT protects neurons and astrocytes against focal cerebral ischemia by inhibiting the expression of NF-κB [22] or through its anti-oxidant and anti-apoptotic properties [23]. Further, MAT treatment improves motor function and increases axonal density in mice with spinal cord injury, likely through inhibition of epidermal growth factor receptor signaling [24]. However, whether MAT can induce neuroregeneration in EAE has not been studied.…”