The Journal of Experimental Medicine
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Published 5 July 2005. doi:10.1084/jem.20041918
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 1, 145-156
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ARTICLE

 Inhibition of astroglial nuclear factor {kappa}B reduces inflammation and improves functional recovery after spinal cord injury

Roberta Brambilla1, Valerie Bracchi-Ricard1, Wen-Hui Hu1, Beata Frydel1, Annmarie Bramwell3, Shaffiat Karmally1, Edward J. Green2,3, and John R. Bethea1,2

1 The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136
2 Neuroscience Program, Miller School of Medicine, University of Miami, Miami, FL 33136
3 Department of Psychology, University of Miami, Miami, FL 33124

CORRESPONDENCE John R. Bethea: JBethea{at}miami.edu OR Roberta Brambilla: r.brambilla{at}miami.edu

In the central nervous system (CNS), the transcription factor nuclear factor (NF)-{kappa}B is a key regulator of inflammation and secondary injury processes. After trauma or disease, the expression of NF-{kappa}B–dependent genes is highly activated, leading to both protective and detrimental effects on CNS recovery. We demonstrate that selective inactivation of astroglial NF-{kappa}B in transgenic mice expressing a dominant negative (dn) form of the inhibitor of {kappa}B{alpha} under the control of an astrocyte-specific promoter (glial fibrillary acidic protein [GFAP]–dn mice) leads to a dramatic improvement in functional recovery 8 wk after contusive spinal cord injury (SCI). Histologically, GFAP mice exhibit reduced lesion volume and substantially increased white matter preservation. In parallel, they show reduced expression of proinflammatory chemokines and cytokines, such as CXCL10, CCL2, and transforming growth factor–ß2, and of chondroitin sulfate proteoglycans participating in the formation of the glial scar. We conclude that selective inhibition of NF-{kappa}B signaling in astrocytes results in protective effects after SCI and propose the NF-{kappa}B pathway as a possible new target for the development of therapeutic strategies for the treatment of SCI.

Abbreviations used: ANOVA, analysis of variance; CNS, central nervous system; CSPG, chondroitin sulfate proteoglycan; dn, dominant negative; EMSA, electrophoretic mobility shift assay; GFAP, glial fibrillary acidic protein; I{kappa}B{alpha}, inhibitor of {kappa}B{alpha}; MBP, myelin basic protein; RPA, RNase protection assay; SCI, spinal cord injury; TG, transgenic; TuJ1, neuronal class III ß-tubulin.

R. Brambilla and V. Bracchi-Ricard contributed equally to this work.

W.-H. Hu's present address is Dept. of Physiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298.


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