Enhancing Nrf2 Pathway by Disruption of Keap1 in Myeloid Leukocytes Protects against Sepsis
Enhancing Nrf2 Pathway by Disruption of Keap1 in Myeloid Leukocytes Protects against Sepsis
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DOI：
10.1164/rccm.201102-0271oc
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发表时间：
2011-10-15
影响因子：
24.7
通讯作者：
Biswal, Shyam
中科院分区：
文献类型：
--
作者：
Kong, Xiaoni;Thimmulappa, Rajesh;Biswal, Shyam
基本原理：脓毒症综合征的特征是不适当的全身炎症反应和菌血症，促进多器官衰竭和死亡率。核因子-红细胞2 p45相关因子2（Nrf 2）调节包括抗氧化剂在内的多效性细胞保护防御程序，并通过抑制氧化性组织损伤来保护免受几种炎性疾病。然而，增强的Nrf 2活性在调节对微生物感染的先天免疫应答和脓毒症发病机制中的作用尚不清楚。目的：确定髓系白细胞中的Nrf 2是否改变炎症反应并保护免受脓毒症。对髓系白细胞中Nrf 2或kelch样ECH相关蛋白（Keap 1）缺失的小鼠和相应的floxed对照进行盲肠结扎和穿孔。诱导脓毒症，并评估存活率、器官损伤、全身炎症和菌血症。使用LPS刺激的腹腔巨噬细胞，分析Toll样受体（TLR）4表面运输和下游信号传导事件。死亡率、器官损伤、炎症介质循环水平，与相应的floxed对照组相比，LysM-Keap 1（-/-）组的细菌感染和菌血症显著减少（Keap 1（f/f）或Nrf 2（f/f）），并且在盲肠结扎和穿刺后在LysM-Nrf 2（-/-）小鼠中显著升高。与LysM-Nrf 2（-/-）和floxed对照相比，脓毒症LysM-Keap 1（-/-）小鼠的腹膜巨噬细胞显示出更大的细菌吞噬活性。LPS刺激导致更多活性氧诱导的细胞表面TLR 4从trans-Golgi网络转运以及随后的TLR 4下游信号转导（MYD 88和TRIF的募集、IkB和IRF 3的磷酸化以及细胞因子表达）。我们的研究表明，Nrf 2在白细胞中作为一种重要的免疫调节剂，控制宿主对细菌感染的炎症反应，并防止脓毒症。
Rationale: Sepsis syndrome is characterized by inappropriate amplified systemic inflammatory response and bacteremia that promote multiorgan failure and mortality. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulates a pleiotropic cytoprotective defense program including antioxidants and protects against several inflammatory disorders by inhibiting oxidative tissue injuries. However, the role of enhanced Nrf2 activity in modulating innate immune responses to microbial infection and pathogenesis of sepsis is unclear.Objectives: To determine whether Nrf2 in myeloid leukocytes alters inflammatory response and protects against sepsis.Methods: Mice with deletion of Nrf2 or kelch-like ECH-associated protein (Keap1) in myeloid leukocyte cells and respective floxed controls were subjected to cecal ligation and puncture-induced sepsis and were assessed for survival, organ injury, systemic inflammation, and bacteremia. Using LPS-stimulated peritoneal macrophages, Toll-like receptor (TLR) 4 surface trafficking and downstream signaling events were analyzed.Measurements and Main Results: Mortality, organ injury, circulating levels of inflammatory mediators, and bacteremia were markedly reduced in LysM-Keap1(-/-) compared with respective floxed controls (Keap1(f/f) or Nrf2(f/f)) and significantly elevated in LysM-Nrf2(-/-) mice after cecal ligation and puncture. Peritoneal macrophages from septic LysM-Keap1(-/-) mice showed a greater bacterial phagocytic activity compared with LysM-Nrf2(-/-) and floxed controls. LPS stimulation resulted in greater reactive oxygen species-induced cell surface transport of TLR4 from trans-Golgi network and subsequent TLR4 downstream signaling (recruitment of MYD88 and TRIF, phosphorylation of IkB and IRF3, and cytokine expression) in macrophages of LysM-Nrf2(-/-) compared with LysM-Keap1(-/-) mice and floxed controls.Conclusions: Our study shows that Nrf2 acts as a critical immunomodulator in leukocytes, controls host inflammatory response to bacterial infection, and protects against sepsis.