Deletion of N-myc downstream-regulated gene 2 attenuates reactive astrogliosis and inflammatory response in a mouse model of cortical stab injury.
N-myc downstream-regulated gene 2 (Ndrg2) is a differentiation- and stress-associated molecule predominantly expressed in astrocytes in the CNS. In this study, we examined the expression and the role of Ndrg2 after cortical stab injury. We observed that Ndrg2 expression was elevated in astrocytes surrounding the wounded area as early as day 1 after injury in wild-type mice. Deletion of Ndrg2 resulted in lower induction of reactive astroglial and microglial markers in the injured cortex. Histological analysis showed reduced levels of hypertrophic changes in astrocytes, accumulation of microglia, and neuronal death in Ndrg2(-/-) mice after injury. Furthermore, activation of the IL-6/signal transducer and activator of transcription 3 (STAT3) pathway, including the expression of IL-6 family cytokines and phosphorylation of STAT3, was markedly reduced in Ndrg2(-/-) mice after injury. In a culture system, both of Il6 and Gfap were up-regulated in wild-type astrocytes treated with forskolin. Deletion of Ndrg2 attenuated induction of these genes, but did not alter proliferation or migration of astrocytes. Adenovirus-mediated reexpression of Ndrg2 rescued the reduction of IL-6 expression after forskolin stimulation. These findings suggest that Ndrg2 plays a key role in reactive astrogliosis after cortical stab injury through a mechanism involving the positive regulation of IL-6/STAT3 signaling.
Department of Neuroanatomy, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan; Japan Science and Technology Agency, CREST, Kawaguchi, Saitama, Japan.
Mika
M
Takarada-Iemata
Dai
D
Kezuka
Toshiaki
T
Takeichi
Masahito
M
Ikawa
Tsuyoshi
T
Hattori
Yasuko
Y
Kitao
Osamu
O
Hori
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D001930:Brain Injuries / Q000235:genetics* / Q000473:pathology*; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000293:injuries*; D005576:Colforsin; D000229:Dependovirus / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D017353:Gene Deletion; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis / Q000378:metabolism; D005911:Gliosis / Q000235:genetics* / Q000473:pathology*; D020197:Head Injuries, Penetrating / Q000235:genetics* / Q000473:pathology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics* / Q000473:pathology*; D015850:Interleukin-6 / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics* / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D014951:Wounds, Stab / Q000235:genetics* / Q000473:pathology*
D048868:Adaptor Proteins, Signal Transducing; D005904:Glial Fibrillary Acidic Protein; D015850:Interleukin-6; C485172:Ndr2 protein, mouse; D011506:Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D005576:Colforsin
brain injury; inflammation; interleukin-6; neuronal death; reactive astrogliosis