Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury.
In the central nervous system (CNS), the transcription factor nuclear factor (NF)-kappaB is a key regulator of inflammation and secondary injury processes. After trauma or disease, the expression of NF-kappaB-dependent genes is highly activated, leading to both protective and detrimental effects on CNS recovery. We demonstrate that selective inactivation of astroglial NF-kappaB in transgenic mice expressing a dominant negative (dn) form of the inhibitor of kappaB 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-beta2, and of chondroitin sulfate proteoglycans participating in the formation of the glial scar. We conclude that selective inhibition of NF-kappaB signaling in astrocytes results in protective effects after SCI and propose the NF-kappaB pathway as a possible new target for the development of therapeutic strategies for the treatment of SCI.
The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Roberta
R
Brambilla
Valerie
V
Bracchi-Ricard
Wen-Hui
WH
Hu
Beata
B
Frydel
Annmarie
A
Bramwell
Shaffiat
S
Karmally
Edward J
EJ
Green
John R
JR
Bethea
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001483:Base Sequence; D018925:Chemokines / Q000378:metabolism; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000172:deficiency / Q000235:genetics; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D015398:Signal Transduction; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*
D018925:Chemokines; D011508:Chondroitin Sulfate Proteoglycans; D016207:Cytokines; D018076:DNA, Complementary; D005904:Glial Fibrillary Acidic Protein; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; C516895:PTPRZ1 protein, human; C516896:Ptprz1 protein, mouse; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5