Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Baltimore, MD 21205, USA.
Am J Respir Crit Care Med. 2011 Oct 15;184(8):928-38. doi: 10.1164/rccm.201102-0271OC. Epub 2011 Jul 28.
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.
To determine whether Nrf2 in myeloid leukocytes alters inflammatory response and protects against sepsis.
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.
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.
Our study shows that Nrf2 acts as a critical immunomodulator in leukocytes, controls host inflammatory response to bacterial infection, and protects against sepsis.
脓毒症综合征的特征是全身炎症反应过度放大和菌血症，从而导致多器官衰竭和死亡。核因子-红细胞 2 p45 相关因子 2（Nrf2）调节包括抗氧化剂在内的多种细胞保护防御程序，并通过抑制氧化组织损伤来保护免受几种炎症性疾病的影响。然而，增强的 Nrf2 活性在调节对微生物感染的固有免疫反应和脓毒症发病机制中的作用尚不清楚。
确定髓样白细胞中的 Nrf2 是否改变炎症反应并预防脓毒症。
对髓样白细胞中 Nrf2 或 Kelch 样 ECH 相关蛋白（Keap1）缺失的小鼠及其相应的 floxed 对照进行盲肠结扎和穿孔诱导的脓毒症，并评估其存活率、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 表面转运和下游信号事件。
盲肠结扎和穿孔后，与相应的 floxed 对照（Keap1(f/f)或 Nrf2(f/f))相比，LysM-Keap1(-/-)小鼠的死亡率、器官损伤、循环炎症介质水平和菌血症明显降低，而 LysM-Nrf2(-/-)小鼠的死亡率、器官损伤、循环炎症介质水平和菌血症明显升高。与 LysM-Nrf2(-/-)和 floxed 对照相比，来自脓毒症 LysM-Keap1(-/-)小鼠的腹腔巨噬细胞显示出更高的细菌吞噬活性。LPS 刺激导致从反式高尔基网络中诱导 TLR4 的活性氧诱导的 TLR4 细胞表面转运，以及随后在 LysM-Nrf2(-/-)与 LysM-Keap1(-/-)小鼠和 floxed 对照相比，TLR4 下游信号（MyD88 和 TRIF 的募集、IkB 和 IRF3 的磷酸化以及细胞因子表达）。
我们的研究表明，Nrf2 作为白细胞中的关键免疫调节剂，控制宿主对细菌感染的炎症反应并预防脓毒症。
