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

Kate L Lambertsen,Ditte G Ellman,Shaffiat Karmally,Joshua Johnstone,Beata Frydel,Jerome Ricard,John R Bethea,Lubov Nathanson,Dana M Mctigue,Valerie Bracchi-Ricard

doi:10.1186/1742-2094-10-92

Abstract

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

Highlights

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
Oligodendrogenesis is increased following spinal cord injury in mice lacking functional Nuclear factor-kappa B (NF-κB) signaling in astrocytes Based on our previous findings of a reduced lesion volume, increased white matter preservation and associated improvements in locomotor function 8 weeks following moderate contusion to the thoracic spinal cord in mice lacking astroglial NF-κB [12], we wanted to investigate the possibility that the observed increase in white matter is due, in part, to enhanced oligodendrogenesis
We found that the spinal cords from naïve WT and IκBα-dn mice appeared morphologically identical [12] and displayed similar numbers of nerve/ glial antigen 2+ (NG2)+ Oligodendrocyte precursor cell (OPC) (WT: 2,479 ± 181; IκBα-dn: 3,397 ± 683, P = 0.23) and CC1+ oligodendrocytes (WT: 59,190 ± 2,086; IκBα-dn: 61,540 ± 2,447, P = 0.504) (Figure 1E)

Summary

Introduction

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. To study the role of astroglial NF-κB in the pathogenesis of SCI, we previously generated transgenic mice (GFAP-IκBα-dn) in which NF-κΒ is inactivated in astrocytes by overexpression of a truncated form of the inhibitor IκBα (IκBα-dn) under the control of the glial fibrillary acidic protein (GFAP) promoter [12]. In this previous study, we demonstrated that blocking NF-κB activation in astrocytes resulted in reduced expression of cytokines and chemokines such as CXCL10, CCL2 and transforming growth factor beta, and in a smaller lesion volume and increased white matter sparing along with a significant improvement in locomotor function following SCI. We are addressing the role of astroglial NF-κB in regulating oligodendrogenesis in the chronically injured spinal cord

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Results

Conclusion