Expression and activation of EphA4 in the human brain after traumatic injury.
Glial scars that consist predominantly of reactive astrocytes create a major barrier to neuronal regeneration after traumatic brain injury (TBI). In experimental TBI, Eph receptors and their ephrin ligands are upregulated on reactive astrocytes at injury sites and inhibit axonal regeneration, but very little is known about Eph receptors in the human brain after TBI. A better understanding of the functions of glial cells and their interactions with inflammatory cells and injured axons will allow the development of treatment strategies that may promote regeneration. We analyzed EphA4 expression and activation in postmortem brain tissue from 19 patients who died after acute closed head injury and had evidence of diffuse axonal injury and 8 controls. We also examined downstream pathways that are mediated by EphA4 in human astrocyte cell cultures. Our results indicate that, after TBI in humans, EphA4 expression is upregulated and is associated with reactive astrocytes. The expression was increased shortly after the injury and remained activated for several days. EphA4 activation induced under inflammatory conditions in vitro was inhibited using unclustered EphA4 ligand. These results suggest that blocking EphA4 activation may represent a therapeutic approach for TBI and other types of brain injuries in humans.
National Trauma Research Instituteand Anatomical Pathology Department (CM), St. Vincent's Hospital, Melbourne, Victoria, Australia.
Tony
T
Frugier
Alison
A
Conquest
Catriona
C
McLean
Peter
P
Currie
David
D
Moses
Yona
Y
Goldshmit
D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001930:Brain Injuries / Q000473:pathology*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D036342:Ephrins / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000494:pharmacology; D019394:Ki-67 Antigen / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D036122:Receptor, EphA4 / Q000378:metabolism*; D013997:Time Factors; D055815:Young Adult; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D036342:Ephrins; D005904:Glial Fibrillary Acidic Protein; D019394:Ki-67 Antigen; D008070:Lipopolysaccharides; D007371:Interferon-gamma; D036122:Receptor, EphA4; D020741:rho GTP-Binding Proteins