Transgenic inhibition of astroglial NF-κB protects from optic nerve damage and retinal ganglion cell loss in experimental optic neuritis

Journal of Neuroinflammation

Valery I Shestopalov³  John R Bethea⁴  Dmitry Ivanov²  David Barakat¹  Galina Dvoriantchikova¹  Roberta Brambilla⁵ 

[1] Department of Ophthalmology, Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA;Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russian Federation;Department of Cell Biology and Anatomy, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA;Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA;Department of Neurological Surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA

关键词: NF-κB pathway;    Retinal ganglion cell death;    Astrogliosis;    Optic neuritis;   

Others  :  1160260
DOI  :  10.1186/1742-2094-9-213

 received in 2012-05-29, accepted in 2012-08-22,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Brambilla et al.; licensee BioMed Central Ltd.

【 图 表 】

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