Inhibition of astroglial NF-kappaB enhances oligodendrogenesis following spinal cord injury

Journal of Neuroinflammation

John R Bethea¹  Dana M McTigue³  Beata Frydel¹  Ditte G Ellman⁴  Joshua Johnstone¹  Shaffiat Karmally¹  Lubov Nathanson²  Jerome Ricard¹  Kate L Lambertsen⁴  Valerie Bracchi-Ricard¹ 

[1] The Miami Project to Cure Paralysis, University of Miami, Miami FL 33136, USA;Department of Molecular and Cellular Medicine, Miller School of Medicine, University of Miami, Miami FL 33136, USA;Department of Neuroscience, The Center for Brain and Spinal Cord Repair, The Ohio State University, 795 12th Avenue, Columbus OH 43210, USA;Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000, Odense, C, Denmark

关键词: Toll-like receptor;    TNFR2;    CXCR4;    Microglia;    Oligodendrocyte;    Astrocyte;    Spinal cord injury;    NF-kappaB;   

Others  :  1152474
DOI  :  10.1186/1742-2094-10-92

 received in 2013-03-04, accepted in 2013-07-12,  发布年份 2013

【 摘 要 】

Background

Astrocytes are taking the center stage in neurotrauma and neurological diseases as they appear to play a dominant role in the inflammatory processes associated with these conditions. Previously, we reported that inhibiting NF-κB activation in astrocytes, using a transgenic mouse model (GFAP-IκBα-dn mice), results in improved functional recovery, increased white matter preservation and axonal sparing following spinal cord injury (SCI). In the present study, we sought to determine whether this improvement, due to inhibiting NF-κB activation in astrocytes, could be the result of enhanced oligodendrogenesis in our transgenic mice.

Methods

To assess oligodendrogenesis in GFAP-IκBα-dn compared to wild-type (WT) littermate mice following SCI, we used bromodeoxyuridine labeling along with cell-specific immuno-histochemistry, confocal microscopy and quantitative cell counts. To further gain insight into the underlying molecular mechanisms leading to increased white matter, we performed a microarray analysis in naïve and 3 days, 3 and 6 weeks following SCI in GFAP-IκBα-dn and WT littermate mice.

Results

Inhibition of astroglial NF-κB in GFAP-IκBα-dn mice resulted in enhanced oligodendrogenesis 6 weeks following SCI and was associated with increased levels of myelin proteolipid protein compared to spinal cord injured WT mice. The microarray data showed a large number of differentially expressed genes involved in inflammatory and immune response between WT and transgenic mice. We did not find any difference in the number of microglia/leukocytes infiltrating the spinal cord but did find differences in their level of expression of toll-like receptor 4. We also found increased expression of the chemokine receptor CXCR4 on oligodendrocyte progenitor cells and mature oligodendrocytes in the transgenic mice. Finally TNF receptor 2 levels were significantly higher in the transgenic mice compared to WT following injury.

Conclusions

These studies suggest that one of the beneficial roles of blocking NF-κB in astrocytes is to promote oligodendrogenesis through alteration of the inflammatory environment.

【 授权许可】

   
2013 Bracchi-Ricard et al.; licensee BioMed Central Ltd.

【 图 表 】

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