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Enhanced Expression of Catalase in Mitochondria Modulates NF-κB–Dependent Lung Inflammation through Alteration of Metabolic Activity in Macrophages
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-06-29 , DOI: 10.4049/jimmunol.1900820
Wei Han 1 , Joshua P Fessel 1, 2 , Taylor Sherrill 1 , Emily G Kocurek 1 , Fiona E Yull 2, 3 , Timothy S Blackwell 4, 5, 6
Affiliation  

Key Points Mitochondrial catalase regulates inflammation by altering cellular metabolism. NAD(H) levels modulate NF-κB activation in macrophages. NF-κB is a reduction-oxidation–sensitive transcription factor that plays a key role in regulating the immune response. In these studies, we intended to investigate the role of mitochondrial-derived reactive oxygen species in regulating NF-κB activation by studying transgenic mice that overexpress mitochondrial-targeted human catalase (mCAT). We treated wild-type (WT) and mCAT mice with intratracheal instillation of Escherichia coli LPS and found that mCAT mice had exaggerated NF-κB activation in the lungs, increased neutrophilic alveolitis, and greater lung inflammation/injury compared with WT mice. Additional studies using bone marrow chimeras revealed that this hyperinflammatory phenotype was mediated by immune/inflammatory cells. Mechanistic studies using bone marrow–derived macrophages (BMDMs) showed that LPS treatment induced a sustained increase in NF-κB activation and expression of NF-κB–dependent inflammatory mediators in mCAT BMDMs compared with WT BMDMs. Further investigations showed that cytoplasmic, but not mitochondrial, hydrogen peroxide levels were reduced in LPS-treated mCAT BMDMs. However, mCAT macrophages exhibited increased glycolytic and oxidative metabolism, coupled with increased ATP production and an increased intracellular NADH/NAD+ ratio compared with BMDMs from WT mice. Treatment of BMDMs with lactate increased the intracellular NADH/NAD+ ratio and upregulated NF-κB activation after LPS treatment, whereas treatment with a potent inhibitor of the mitochondrial pyruvate carrier (UK5099) decreased the NADH/NAD+ ratio and reduced NF-κB activation. Taken together, these findings point to an increased availability of reducing equivalents in the form of NADH as an important mechanism by which metabolic activity modulates inflammatory signaling through the NF-κB pathway.

中文翻译:

线粒体中过氧化氢酶表达的增强通过改变巨噬细胞的代谢活性来调节 NF-κB 依赖性肺部炎症

要点线粒体过氧化氢酶通过改变细胞代谢来调节炎症。NAD(H) 水平调节巨噬细胞中 NF-κB 的激活。NF-κB 是一种氧化还原敏感转录因子,在调节免疫反应中发挥关键作用。在这些研究中,我们打算通过研究过度表达线粒体靶向人过氧化氢酶 (mCAT) 的转基因小鼠来研究线粒体衍生的活性氧在调节 NF-κB 激活中的作用。我们通过气管内滴注大肠杆菌 LPS 治疗野生型 (WT) 和 mCAT 小鼠,发现与 WT 小鼠相比,mCAT 小鼠肺部 NF-κB 激活过度,中性粒细胞性肺泡炎增加,肺部炎症/损伤更严重。使用骨髓嵌合体的其他研究表明,这种高炎症表型是由免疫/炎症细胞介导的。使用骨髓源性巨噬细胞 (BMDM) 进行的机制研究表明,与 WT BMDM 相比,LPS 治疗可诱导 mCAT BMDM 中 NF-κB 活化和 NF-κB 依赖性炎症介质表达持续增加。进一步的研究表明,LPS 处理的 mCAT BMDM 中细胞质而非线粒体的过氧化氢水平降低。然而,与 WT 小鼠的 BMDM 相比,mCAT 巨噬细胞表现出糖酵解和氧化代谢增加,同时 ATP 产生增加,细胞内 NADH/NAD+ 比率增加。用乳酸处理 BMDM 后,LPS 处理后会增加细胞内 NADH/NAD+ 比率并上调 NF-κB 活化,而用线粒体丙酮酸载体的有效抑制剂 (UK5099) 处理会降低 NADH/NAD+ 比率并减少 NF-κB 活化。总而言之,这些发现表明 NADH 形式的还原当量的可用性增加,作为代谢活动通过 NF-κB 途径调节炎症信号传导的重要机制。
更新日期:2020-06-29
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