Deletion of N‐myc downstream‐regulated gene 2 attenuates reactive astrogliosis and inflammatory response in a mouse model of cortical stab injury

• Published in: Journal of neurochemistry 2014-08, Vol.130 (3), p.374-387
• Main Authors: Takarada‐Iemata, Mika, Kezuka, Dai, Takeichi, Toshiaki, Ikawa, Masahito, Hattori, Tsuyoshi, Kitao, Yasuko, Hori, Osamu
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes - pathology; Brain damage; Brain Injuries - genetics; Brain Injuries - pathology; brain injury; Cell Death - genetics; Cell Death - physiology; Cells, Cultured; Cerebral Cortex - injuries; Colforsin; Dependovirus - genetics; Enzyme-Linked Immunosorbent Assay; Gene Deletion; Genes; Glial Fibrillary Acidic Protein - biosynthesis; Glial Fibrillary Acidic Protein - metabolism; Gliosis - genetics; Gliosis - pathology; Head Injuries, Penetrating - genetics; Head Injuries, Penetrating - pathology; Immunohistochemistry; inflammation; Inflammation - genetics; Inflammation - pathology; Interleukin-6 - physiology; interleukin‐6; Male; Medical research; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurochemistry; neuronal death; Polymerase Chain Reaction; Proteins - genetics; Proteins - physiology; reactive astrogliosis; Real-Time Polymerase Chain Reaction; Signal Transduction; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - physiology; Wounds, Stab - genetics; Wounds, Stab - pathology
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12729

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. Astrocytes play a key role in central nervous system (CNS) injury. We demonstrate that Ndrg2 (N‐myc downstream‐regulated gene 2) is up‐regulated in the early phase after brain injury, and that its deletion alters astrogliosis, inflammation, and neuronal death in vivo. The function of Ndrg2 could correlate with the interleukin IL‐6 pathway in astrocytes. Our findings have important implications for the modulation of inflammation in the CNS. Astrocytes play a key role in central nervous system (CNS) injury. We demonstrate that Ndrg2 (N‐myc downstream‐regulated gene 2) is up‐regulated in the early phase after brain injury, and that its deletion alters astrogliosis, inflammation, and neuronal death in vivo. The function of Ndrg2 could correlate with the interleukin IL‐6 pathway in astrocytes. Our findings have important implications for the modulation of inflammation in the CNS.