ATF3-Mediated NRF2/HO-1 Signaling Regulates TLR4 Innate Immune Responses in Mouse Liver Ischemia/Reperfusion Injury
ATF3-Mediated NRF2/HO-1 Signaling Regulates TLR4 Innate Immune Responses in Mouse Liver Ischemia/Reperfusion Injury
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DOI：
10.1111/ajt.12954
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发表时间：
2015-01-01
影响因子：
8.8
通讯作者：
Lu, L.
中科院分区：
文献类型：
--
作者：
Rao, J.;Qian, X.;Lu, L.
激活转录因子3（ATF 3）是一种应激诱导的转录因子，已显示其在多种细胞类型和疾病中抑制炎性基因表达。然而，ATF 3在肝脏缺血/再灌注损伤（IRI）中的作用和机制尚不清楚。在热肝和冷肝IRI模型中，我们发现ATF 3缺乏显著增加了缺血/再灌注（IR）应激性肝损伤，如血清丙氨酸氨基转移酶水平升高、组织学肝损伤和肝细胞凋亡所证明。这些可能与抑制肝内核因子红细胞衍生2相关因子2/血红素加氧酶-1（NRF 2/HO-1）信号通路相关，从而增强Toll样受体4/核因子κ β（TLR 4/NF-B）活化、促炎程序和巨噬细胞/中性粒细胞运输，同时抑制缺血性肝脏中的抗凋亡分子。有趣的是，在ATF 3缺陷小鼠中，使用NRF 2激活剂奥替普拉（M2）激活NRF 2/HO-1信号传导在肝脏IRI期间拯救了ATF 3抗炎功能。在体外研究中，脂多糖（LPS）刺激的骨髓源性巨噬细胞（BCG）中的ATF 3消融降低了NRF 2/HO-1和PI 3 K/AKT的水平，导致TLR 4/NF-B活化增强。M2预处理LPS刺激的BMPs可增加NRF 2/HO-1表达，促进PI 3 K/AKT，进而抑制TLR 4/NF-B介导的促炎介质。因此，我们的研究结果首次证明了ATF 3介导的NRF 2/HO-1信号在IR应激肝脏中调节TLR 4驱动的炎症反应。我们的研究结果提供了一个新的治疗策略，用于管理IR诱导的肝injuries.This研究表明，激活转录因子3调节Toll样受体4驱动的炎症反应，核因子红细胞衍生的2相关因子2/血红素加氧酶-1，减轻肝脏缺血再灌注损伤。
Activating transcription factor 3 (ATF3) is a stress-induced transcription factor that has been shown to repress inflammatory gene expression in multiple cell types and diseases. However, little is known about the roles and mechanisms of ATF3 in liver ischemia/reperfusion injury (IRI). In warm and cold liver IRI models, we showed that ATF3 deficiency significantly increased ischemia/reperfusion (IR)-stressed liver injury, as evidenced by increased serum alanine aminotransferase levels, histological liver damage, and hepatocellular apoptosis. These may correlate with inhibition of the intrahepatic nuclear factor erythroid-derived 2-related factor 2/heme oxygenase-1 (NRF2/HO-1) signaling pathway leading to enhancing Toll-like receptor 4/nuclear factor kappa beta (TLR4/NF-B) activation, pro-inflammatory programs and macrophage/neutrophil trafficking, while simultaneously repressing anti-apoptotic molecules in ischemic liver. Interestingly, activation of NRF2/HO-1 signaling using an NRF2 activator, oltipraz (M2), during hepatic IRI-rescued ATF3 anti-inflammatory functions in ATF3-deficient mice. For in vitro studies, ATF3 ablation in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMMs) depressed levels of NRF2/HO-1 and PI3K/AKT, resulting in enhanced TLR4/NF-B activation. Pretreatment of LPS-stimulated BMMs with M2 increased NRF2/HO-1 expression, promoted PI3K/AKT, which in turn suppressed TLR4/NF-B-mediated proinflammatory mediators. Thus, our results first demonstrate ATF3-mediated NRF2/HO-1 signaling in the regulation of TLR4-driven inflammatory responses in IR-stressed livers. Our findings provide a rationale for a novel therapeutic strategy for managing IR-induced liver injury.This study demonstrates that activating transcription factor 3 regulates toll-like receptor 4-driven inflammatory responses by nuclear factor erythroid-derived 2-related factor 2/heme oxygenase-1, and attenuates liver ischemia reperfusion injury.