Myeloid-Specific Blockade of Notch Signaling by RBP-J Knockout Attenuates Spinal Cord Injury Accompanied by Compromised Inflammation Response in Mice
Myeloid-Specific Blockade of Notch Signaling by RBP-J Knockout Attenuates Spinal Cord Injury Accompanied by Compromised Inflammation Response in Mice
复制标题
通过 RBP-J 敲除对 Notch 信号传导进行骨髓特异性阻断可减轻小鼠脊髓损伤并伴有炎症反应受损
DOI：
10.1007/s12035-014-8934-z
复制
发表时间：
2015-12-01
影响因子：
5.1
通讯作者：
Han, Hua
中科院分区：
文献类型：
--
作者：
Chen, Bei-Yu;Zheng, Min-Hua;Han, Hua
脊髓损伤（SCI）的结果由神经细胞内在的存活通路和组织微环境衍生的信号共同决定。在脊髓损伤中主导炎症反应的巨噬细胞根据其激活状态具有破坏和修复两种潜能。Notch信号通路参与细胞存活和巨噬细胞介导的炎症，但Notch信号在脊髓损伤中的全面作用一直难以捉摸。在本研究中，我们比较了药物性γ-分泌酶抑制剂（GSI）对Notch信号的全面阻断以及重组信号结合蛋白Jκ（RBP - J）基因敲除对髓系细胞中Notch信号的特异性破坏对脊髓损伤的影响。给予Notch信号抑制剂GSI导致后肢运动能力恶化，炎症加剧。然而，在髓系细胞中缺乏RBP - J（介导所有四种哺乳动物Notch受体信号的关键转录因子）的小鼠在脊髓损伤后表现出功能恢复改善、胶质瘢痕形成减轻、神经元存活和轴突再生提高以及炎症反应缓解。这些益处伴随着脊髓损伤后损伤区域AKT激活增强。这些发现表明，阻断髓系细胞中的Notch信号可改善脊髓损伤后的炎症反应并促进功能恢复，但药物对Notch信号的全面阻断具有相反的效果。因此，对脊髓损伤中Notch信号的临床干预需要明确针对髓系细胞，以避免全面抑制产生的反作用。
The outcome of spinal cord injury (SCI) is determined by both neural cell-intrinsic survival pathways and tissue microenvironment-derived signals. Macrophages dominating the inflammatory responses in SCI possess both destructive and reparative potentials, according to their activation status. Notch signaling is involved in both cell survival and macrophage-mediated inflammation, but a comprehensive role of Notch signaling in SCI has been elusive. In this study, we compared the effects of general Notch blockade by a pharmaceutical γ-secretase inhibitor (GSI) and myeloid-specific Notch signal disruption by recombination signal binding protein Jκ (RBP-J) knockout on SCI. The administration of Notch signal inhibitor GSI resulted in worsened hind limb locomotion and exacerbated inflammation. However, mice lacking RBP-J, the critical transcription factor mediating signals from all four mammalian Notch receptors, in myeloid lineage displayed promoted functional recovery, attenuated glial scar formation, improved neuronal survival and axon regrowth, and mitigated inflammatory response after SCI. These benefits were accompanied by enhanced AKT activation in the lesion area after SCI. These findings demonstrate that abrogating Notch signal in myeloid cells ameliorates inflammation response post-SCI and promotes functional recovery, but general pharmaceutical Notch interception has opposite effects. Therefore, clinical intervention of Notch signaling in SCI needs to pinpoint myeloid lineage to avoid the counteractive effects of global inhibition.