J Clin Invest. 2014 Feb;124(2):730-41. doi: 10.1172/JCI70812. Epub 2014 Jan 27.
A nuclear disaster may result in exposure to potentially lethal doses of ionizing radiation (IR). Hematopoietic acute radiation syndrome (H-ARS) is characterized by severe myelosuppression, which increases the risk of infection, bleeding, and mortality. Here, we determined that activation of nuclear factor erythroid-2-related factor 2 (NRF2) signaling enhances hematopoietic stem progenitor cell (HSPC) function and mitigates IR-induced myelosuppression and mortality. Augmenting NRF2 signaling in mice, either by genetic deletion of the NRF2 inhibitor Keap1 or by pharmacological NRF2 activation with 2-trifluoromethyl-2'-methoxychalone (TMC), enhanced hematopoietic reconstitution following bone marrow transplantation (BMT). Strikingly, even 24 hours after lethal IR exposure, oral administration of TMC mitigated myelosuppression and mortality in mice. Furthermore, TMC administration to irradiated transgenic Notch reporter mice revealed activation of Notch signaling in HSPCs and enhanced HSPC expansion by increasing Jagged1 expression in BM stromal cells. Administration of a Notch inhibitor ablated the effects of TMC on hematopoietic reconstitution. Taken together, we identified a mechanism by which NRF2-mediated Notch signaling improves HSPC function and myelosuppression following IR exposure. Our data indicate that targeting this pathway may provide a countermeasure against the damaging effects of IR exposure.
核灾难可能导致人体暴露于潜在致死剂量的电离辐射 (IR) 中。造血急性辐射综合征 (H-ARS) 的特征是严重的骨髓抑制，这增加了感染、出血和死亡的风险。在这里，我们确定核因子红细胞 2 相关因子 2 (NRF2) 信号的激活增强了造血干细胞祖细胞 (HSPC) 的功能，并减轻了 IR 引起的骨髓抑制和死亡率。通过基因敲除 NRF2 抑制剂 Keap1 或用 2-三氟甲基-2'-甲氧基查耳酮 (TMC) 进行药理学 NRF2 激活，增强了骨髓移植 (BMT) 后的造血重建。令人惊讶的是，即使在致命的 IR 暴露 24 小时后，TMC 的口服给药也减轻了小鼠的骨髓抑制和死亡率。此外，TMC 给药给辐照的转基因 Notch 报告小鼠揭示了 Notch 信号在 HSPC 中的激活，并通过增加 BM 基质细胞中 Jagged1 的表达来增强 HSPC 扩增。Notch 抑制剂的给药消除了 TMC 对造血重建的影响。总之，我们确定了一种机制，即 NRF2 介导的 Notch 信号通过改善 HSPC 功能和减轻 IR 暴露后的骨髓抑制来发挥作用。我们的数据表明，靶向该途径可能为对抗 IR 暴露的破坏性影响提供一种对策。
