Critical Role of Nrf2 in Innate Immune Response and Survival During Sepsis

描述(申请人提供)：我们的长期目标是了解调节全身炎症和脓毒症发病机制的宿主因素，脓毒症每年仅在美国就影响75万人，并在全球范围内导致高死亡率。我们最近发现了一种新的宿主因子，核因子-红系P45相关因子2(NRF2)，它通过调节控制保护性细胞抗氧化剂诱导的代偿途径，在决定脓毒症的易感性方面发挥关键作用。NRF2是一种碱性亮氨酸拉链转录因子，调节抗氧化基因的表达，包括谷胱甘肽途径和血红素加氧酶，以应对氧化和炎症应激。与野生型小鼠(Nrf2+/+)相比，盲肠结扎穿孔(CLP)和内毒素治疗(Nrf2+/+)后，Nrf2(Nrf2-/-)的整体中断显著降低了存活率。我们假设Nrf2调节一种宿主代偿机制，导致抗氧化剂基因的转录诱导，这决定了脓毒症期间的生存。破坏依赖于Nrf2的代偿性抗氧化途径，通过夸大先天免疫反应，并使淋巴细胞增加凋亡，从而增加死亡率。这一建议将阐明Nrf2对CLP后脓毒症免疫发病机制和生存的依赖调节，并努力开发一种针对Nrf2的新型小分子激活剂的干预策略。具体目标1：验证Nrf2通过维持细胞氧化还原平衡来防止先天性免疫反应放松而决定CLP后存活率的假设。特定目的2：验证Nrf2通过减少淋巴细胞凋亡而提高CLP后存活率的假说。具体目标3：验证小分子激活剂通过增加Nrf2活性来干预脓毒症的假说。脓毒症的免疫发病机制仍然知之甚少。NRF2在氧化应激调节、先天免疫反应和脓毒症存活率之间提供了一种新的联系。这些研究可能导致以Nrf2为基础的干预脓毒症和提高存活率的新策略的开发。

DESCRIPTION (provided by applicant): Our long-term objective is to understand the host factors that regulate the systemic inflammation and pathogenesis of sepsis, which affects 750,000 persons every year in United States alone and causes high mortality worldwide. We recently discovered a novel host factor, nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) that plays a critical role in determining susceptibility to sepsis by regulating a compensatory pathway that controls the induction of protective cellular antioxidants. Nrf2 is a basic leucine zipper transcription factor that regulates the expression of antioxidant genes including the glutathione pathway and heme oxygenase in response to oxidative and inflammatory stress. Global disruption of Nrf2 (Nrf2 -/-) dramatically decreased survival after cecal ligation and puncture (CLP) and endotoxin treatment relative to wild-type mice (Nrf2 +/+). We hypothesize that Nrf2 regulates a host compensatory mechanism that causes transcriptional induction of antioxidant genes, which determines survival during sepsis. Disruption of Nrf2-dependent compensatory antioxidant pathways increases mortality by exaggerating the innate immune response and predisposing lymphocytes to increase apoptosis. This proposal will shed light on the Nrf2-dependent regulation of immunopathogenesis of sepsis and survival after CLP and strives to develop an intervention strategy targeting Nrf2 with a novel small-molecule activator. Specific Aim 1: To test the hypothesis that Nrf2 determines survival after CLP by protecting against deregulation of innate immune response by maintaining cellular redox balance. Specific Aim 2: To test the hypothesis that Nrf2 improves survival after CLP by attenuating apoptosis of lymphocytes. Specific Aim 3: To test the hypothesis of intervening sepsis by increasing Nrf2 activity with a small-molecule activator. The immunopathogenesis of sepsis remains poorly understood. Nrf2 provides a novel link between the regulation of oxidative stress, the innate immune response.and survival during sepsis. These studies may lead to the development of novel strategies based on Nrf2 for intervening in sepsis and improving survival.