NOX4 Mediates Pseudomonas aeruginosa-Induced Nuclear Reactive Oxygen Species Generation and Chromatin Remodeling in Lung Epithelium.
NOX4 Mediates Pseudomonas aeruginosa-Induced Nuclear Reactive Oxygen Species Generation and Chromatin Remodeling in Lung Epithelium.
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DOI：
10.3390/antiox10030477
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发表时间：
2021-03-17
期刊：
影响因子：
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通讯作者：
Natarajan V
中科院分区：
文献类型：
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作者：
Fu P;Ramchandran R;Sudhadevi T;Kumar PPK;Krishnan Y;Liu Y;Zhao Y;Parinandi NL;Harijith A;Sadoshima J;Natarajan V
铜绿假单胞菌 (PA) 感染会增加活性氧 (ROS)，早些时候，我们已经证明 NADPH 氧化酶衍生的 ROS 在 PA 介导的肺部炎症和损伤中发挥作用。在这里，我们展示了肺上皮细胞 (LEpC) NOX4 在 PA 介导的染色质重塑和肺部炎症中的作用。 Nox4flox/flox小鼠气管内给予PA 24 h引起肺部炎症损伤；然而，上皮细胞缺失的Nox4小鼠表现出肺部炎症损伤、氧化应激、促炎细胞因子分泌减少以及组蛋白乙酰化减少。在 LEpC 中，NOX4 定位于细胞质和核部分，PA 刺激增加了核 NOX4 表达和 ROS 产生。 NOX4 和 PKC δ 的下调或抑制会减弱 PA 诱导的核 ROS。与 Nox2 不同，PA 诱导的组蛋白乙酰化可被 Nox4 特异性 siRNA 减弱。 PA 刺激增加 HDAC1/2 氧化并降低 HDAC1/2 活性。 PA 诱导的 HDAC2 氧化可被 N-乙酰基-L-半胱氨酸和 Pkc δ、Sphk2 和 Nox4 特异性的 siRNA 减弱。 PA 刺激细胞核中 RAC1 的激活，并增强 LEpC 中 HDAC2 与 RAC1、p-PKC δ 和 NOX4 之间的关联。我们的结果揭示了肺泡上皮 NOX4 通过核 ROS 生成、HDAC1/2 氧化和染色质重塑介导 PA 诱导的肺部炎症损伤中的关键作用。
Pseudomonas aeruginosa (PA) infection increases reactive oxygen species (ROS), and earlier, we have shown a role for NADPH oxidase-derived ROS in PA-mediated lung inflammation and injury. Here, we show a role for the lung epithelial cell (LEpC) NOX4 in PA-mediated chromatin remodeling and lung inflammation. Intratracheal administration of PA to Nox4flox/flox mice for 24 h caused lung inflammatory injury; however, epithelial cell-deleted Nox4 mice exhibited reduced lung inflammatory injury, oxidative stress, secretion of pro-inflammatory cytokines, and decreased histone acetylation. In LEpCs, NOX4 was localized both in the cytoplasmic and nuclear fractions, and PA stimulation increased the nuclear NOX4 expression and ROS production. Downregulation or inhibition of NOX4 and PKC δ attenuated the PA-induced nuclear ROS. PA-induced histone acetylation was attenuated by Nox4-specific siRNA, unlike Nox2. PA stimulation increased HDAC1/2 oxidation and reduced HDAC1/2 activity. The PA-induced oxidation of HDAC2 was attenuated by N-acetyl-L-cysteine and siRNA specific for Pkc δ, Sphk2, and Nox4. PA stimulated RAC1 activation in the nucleus and enhanced the association between HDAC2 and RAC1, p-PKC δ, and NOX4 in LEpCs. Our results revealed a critical role for the alveolar epithelial NOX4 in mediating PA-induced lung inflammatory injury via nuclear ROS generation, HDAC1/2 oxidation, and chromatin remodeling.