一种小分子 Keap1-Nrf2 相互作用抑制剂通过选择性增强感染部位巨噬细胞的抗菌防御作用来减轻脓毒症。
A small-molecule inhibitor of Keap1-Nrf2 interaction attenuates sepsis by selectively augmenting the antibacterial defence of macrophages at infection sites.
机构信息
Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400038, China; Department of Pulmonary and Critical Care Medicine, General Hospital of Western Theater Command, Chengdu, Sichuan, 610083, China.
Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400038, China; Oncology Department, General Hospital of Western Theater Command, Chengdu, Sichuan, 610083, China.
出版信息
EBioMedicine. 2023 Apr;90:104480. doi: 10.1016/j.ebiom.2023.104480. Epub 2023 Feb 28.
BACKGROUND
Macrophages at infection sites are considered as the promising therapeutic targets to prevent sepsis development. The Nrf2/Keap1 system acts as a critical modulator of the antibacterial activity of macrophages. Recently, Keap1-Nrf2 protein-protein interaction (PPI) inhibitors have emerged as safer and stronger Nrf2 activators; however, their therapeutic potential in sepsis remains unclear. Herein, we report a unique heptamethine dye, IR-61, as a Keap1-Nrf2 PPI inhibitor that preferentially accumulates in macrophages at infection sites.
METHODS
A mouse model of acute lung bacterial infection was used to investigate the biodistribution of IR-61. SPR study and CESTA were used to detect the Keap1 binding behaviour of IR-61 in vitro and in cells. Established models of sepsis in mice were used to determine the therapeutic effect of IR-61. The relationship between Nrf2 levels and sepsis outcomes was preliminarily investigated using monocytes from human patients.
FINDINGS
Our data showed that IR-61 preferentially accumulated in macrophages at infection sites, enhanced bacterial clearance, and improved outcomes in mice with sepsis. Mechanistic studies indicated that IR-61 potentiated the antibacterial function of macrophages by activating Nrf2 via direct inhibition of the Keap1-Nrf2 interaction. Moreover, we observed that IR-61 enhanced the phagocytic ability of human macrophages, and the expression levels of Nrf2 in monocytes might be associated with the outcomes of sepsis patients.
INTERPRETATIONS
Our study demonstrates that the specific activation of Nrf2 in macrophages at infection sites is valuable for sepsis management. IR-61 may prove to be a Keap1-Nrf2 PPI inhibitor for the precise treatment of sepsis.
FUNDING
This work was supported by the National Natural Science Foundation of China (Major program 82192884), the Intramural Research Project (Grants: 2018-JCJQ-ZQ-001 and 20QNPY018), and the Chongqing National Science Foundation (CSTB2022NSCQ-MSX1222).
背景
感染部位的巨噬细胞被认为是预防败血症发展的有前途的治疗靶点。Nrf2/Keap1 系统是调节巨噬细胞抗菌活性的关键调节剂。最近，Keap1-Nrf2 蛋白-蛋白相互作用（PPI）抑制剂作为更安全、更强的 Nrf2 激活剂而出现；然而，它们在败血症中的治疗潜力尚不清楚。在此，我们报告了一种独特的七甲川染料 IR-61，它是一种 Keap1-Nrf2 PPI 抑制剂，优先积聚在感染部位的巨噬细胞中。
方法
采用急性肺部细菌感染的小鼠模型研究 IR-61 的体内分布。SPR 研究和 CESTA 用于检测 IR-61 在体外和细胞中的 Keap1 结合行为。采用小鼠败血症模型确定 IR-61 的治疗效果。使用来自人类患者的单核细胞初步研究了 Nrf2 水平与败血症结果之间的关系。
结果
我们的数据表明，IR-61 优先积聚在感染部位的巨噬细胞中，增强了细菌清除，并改善了败血症小鼠的结局。机制研究表明，IR-61 通过直接抑制 Keap1-Nrf2 相互作用，激活 Nrf2 增强了巨噬细胞的抗菌功能。此外，我们观察到 IR-61 增强了人巨噬细胞的吞噬能力，单核细胞中 Nrf2 的表达水平可能与败血症患者的结局有关。
解释
我们的研究表明，在感染部位特异性激活巨噬细胞中的 Nrf2 对于败血症的治疗具有重要意义。IR-61 可能成为一种 Keap1-Nrf2 PPI 抑制剂，用于精确治疗败血症。
资金
本工作得到了国家自然科学基金重大项目（82192884）、院内研究项目（资助：2018-JCJQ-ZQ-001 和 20QNPY018）和重庆市自然科学基金（CSTB2022NSCQ-MSX1222）的支持。
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