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Wnt5a/Ror2 promotes Nrf2‐mediated tissue protective function of astrocytes after brain injury

生物 细胞生物学 转录因子 血红素加氧酶 星形胶质细胞 信号转导 Wnt信号通路 血红素 成纤维细胞生长因子 神经科学 中枢神经系统 基因 受体 生物化学
作者
Mitsuharu Endo,Yuki Tanaka,Mayo Fukuoka,Hayata Suzuki,Yasuhiro Minami
出处
期刊:Glia [Wiley]
卷期号:72 (2): 411-432
标识
DOI:10.1002/glia.24483
摘要

Abstract Astrocytes, a type of glial cells, play critical roles in promoting the protection and repair of damaged tissues after brain injury. Inflammatory cytokines and growth factors can affect gene expression in astrocytes in injured brains, but signaling pathways and transcriptional mechanisms that regulate tissue protective functions of astrocytes are still poorly understood. In this study, we investigated the molecular mechanisms regulating the function of reactive astrocytes induced in mouse models of stab wound (SW) brain injury and collagenase‐induced intracerebral hemorrhage (ICH). We show that basic fibroblast growth factor (bFGF), whose expression is up‐regulated in mouse brains after SW injury and ICH, acts synergistically with inflammatory cytokines to activate E2F1‐mediated transcription of a gene encoding the Ror‐family protein Ror2, a receptor for Wnt5a, in cultured astrocytes. We also found that subsequent activation of Wnt5a/Ror2 signaling in astrocytes results in nuclear accumulation of antioxidative transcription factor Nrf2 at least partly by increased expression of p62/Sqstm1, leading to promoted expression of several Nrf2 target genes, including heme oxygenase 1 . Finally, we provide evidence demonstrating that enhanced activation of Wnt5a/Ror2 signaling in astrocytes reduces cellular damage caused by hemin, a degradation product of hemoglobin, and promotes repair of the damaged blood brain barrier after brain hemorrhage.
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