Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis
Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis
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DOI：
10.1172/jci25790
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发表时间：
2006-04-01
影响因子：
15.9
通讯作者：
Biswal, S
中科院分区：
文献类型：
--
作者：
Thimmulappa, RK;Lee, H;Biswal, S
调节先天免疫的宿主遗传因素决定对脓毒症的易感性。核因子-红细胞2相关因子2（Nrf 2）是一种调节氧化还原平衡和应激反应的碱性亮氨酸拉链转录因子，其破坏可显著增加内毒素和盲肠结扎及穿孔诱导的脓毒性休克小鼠的死亡率。LPS以及TNF-α刺激导致Nrf 2缺陷小鼠中更大的肺部炎症。LPS激发后肺整体基因表达的时间分析显示，早在30分钟时，Nrf 2缺陷小鼠肺中与先天免疫应答相关的大量促炎基因的表达增加，表明严重的免疫失调。表达谱表明Nrf 2对MyD 88依赖性和非依赖性信号传导具有全局影响。Nrf 2缺陷的小鼠胚胎成纤维细胞表现出更大的激活NF-κ B和干扰素调节因子3响应于LPS和聚肌胞苷酸[poly（I：C）]刺激，证实了Nrf 2对MyD 88依赖性和非依赖性信号传导的影响。Nrf 2对细胞谷胱甘肽和其他抗氧化剂的调节对于响应于LPS和TNF-α的最佳NF-κ B活化至关重要。我们的研究揭示了Nrf 2作为一种新的脓毒症修饰基因，通过建立适当的先天免疫反应来决定生存。
Host genetic factors that regulate innate immunity determine susceptibility to sepsis. Disruption of nuclear factor-erythroid 2-related factor 2 (Nrf2), a basic leucine zipper transcription factor that regulates redox balance and stress response, dramatically increased the mortality of mice in response to endotoxin- and cecal ligation and puncture-induced septic shock. LPS as well as TNF-alpha stimulus resulted in greater lung inflammation in Nrf2-deficient mice. Temporal analysis of pulmonary global gene expression after LPS challenge revealed augmented expression of large numbers of proinflammatory genes associated with the innate immune response at as early as 30 minutes in lungs of Nrf2-deficient mice, indicating severe immune dysregulation. The expression profile indicated that Nrf2 has a global influence on both MyD88-dependent and -independent signaling. Nrf2-deficient mouse embryonic fibroblasts showed greater activation of NF-kappa B and interferon regulatory factor 3 in response to LPS and polyinosinic-polycytidylic acid [poly(I:C)] stimulus, corroborating the effect of Nrf2 on MyD88-dependent and -independent signaling. Nrf2's regulation of cellular glutathione and other antioxidants is critical for optimal NF-kappa B activation in response to LPS and TNF-alpha. Our study reveals Nrf2 as a novel modifier gene of sepsis that determines survival by mounting an appropriate innate immune response.