Astrocytic CCAAT/Enhancer-Binding Protein Delta Contributes to Glial Scar Formation and Impairs Functional Recovery After Spinal Cord Injury.
After spinal cord injury, inflammatory reaction induces the aggregation of astrocytes to form a glial scar that eventually blocks axonal regeneration. Transcription factor CCAAT/enhancer-binding protein delta (C/EBPδ) is a regulatory protein of genes responsive to inflammatory factors, but its role in glial scar formation after spinal cord injury remains unknown. By using a model of moderate spinal cord contusion injury at the mid-thoracic level, we found that C/EBPδ was expressed mostly in the reactive astrocytes bordering the lesion in wild-type mice from 7 days after the injury. C/EBPδ-deficient mice showed reduced glial scar formation, more residual white matter, and better motor function recovery compared with wild-type mice 28 days after the injury. Upon interleukin (IL)-1β stimulation in vitro, the increased expression of C/EBPδ in reactive astrocytes inhibited RhoA expression and, subsequently, the ability of astrocyte migration. However, these reactive astrocytes also produced an increased amount of matrix metalloproteinase-3, which promoted the migration of non-IL-1β-treated, inactive astrocytes. Although the involvement of other non-astroglial C/EBPδ cannot be entirely excluded, our studies suggest that astrocytic C/EBPδ is integral to the inflammatory cascades leading to glial scar formation after spinal cord injury.
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
Shao-Ming
SM
Wang
Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
Jung-Yu C
JC
Hsu
Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, 110, Taiwan.|Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan.
Chiung-Yuan
CY
Ko
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
Nai-En
NE
Chiu
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
Wai-Ming
WM
Kan
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. a1211207@mail.ncku.edu.tw.
Ming-Derg
MD
Lai
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. wwwjm4721@yahoo.com.tw.|Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 701, Taiwan. wwwjm4721@yahoo.com.tw.|Center of Molecular Inflammation, National Cheng Kung University, Tainan, 701, Taiwan. wwwjm4721@yahoo.com.tw.|Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, 110, Taiwan. wwwjm4721@yahoo.com.tw.
Ju-Ming
JM
Wang
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000172:deficiency / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002921:Cicatrix / Q000378:metabolism / Q000473:pathology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009043:Motor Activity / Q000187:drug effects; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology*; D020127:Recovery of Function / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology*; D066127:White Matter / Q000473:pathology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D017077:Culture Media, Conditioned; D005904:Glial Fibrillary Acidic Protein; D053583:Interleukin-1beta; D051743:CCAAT-Enhancer-Binding Protein-delta; D019278:Matrix Metalloproteinase 3; D020742:rhoA GTP-Binding Protein
Astrocyte migration; Astrogliosis; C/EBPδ; MMP-3; RhoA