Research Center for Natural Human Defense System, Yonsei University College of Medicine, Seoul, South Korea.
Antioxid Redox Signal. 2012 Jan 1;16(1):57-70. doi: 10.1089/ars.2011.3898. Epub 2011 Aug 8.
Airway mucosa is constantly exposed to various airborne microbes, and epithelial host defense requires a robust innate immunity. Recently, it has been suggested that NADPH oxidase (NOX) isozymes serve functional roles in toll-like receptor (TLR)-mediated innate immune responses. However, the molecular mechanism between TLR and NOX-mediated reactive oxygen species (ROS) production in human airway mucosa has been poorly understood.
Here, we show that flagellin-induced ROS generation is dependent on dual oxidase 2 (DUOX2) activation, which is regulated by Ca(2+) mobilization in primary normal human nasal epithelial (NHNE) cells. Interestingly, we observed that silencing of DUOX2 expression in NHNE cells and nasal epithelium of Duox2 knockout mice failed to trigger mucin and MIP-2? production upon challenging flagellin.
Our observation in this study reveals that flagellin-induced hydrogen peroxide (H(2)O(2)) generation is critical for TLR5-dependent innate immune responses, including IL-8 production and MUC5AC expression in the nasal epithelium. Furthermore, DUOX2-mediated H(2)O(2) generation activated by the flagellin-TLR5 axis might serve as a novel therapeutic target for infectious inflammation diseases in the airway tract.
Taken together, we propose that DUOX2 plays pivotal roles in TLR5-dependent inflammatory response of nasal airway epithelium.
气道黏膜不断暴露于各种空气传播的微生物中，上皮宿主防御需要强大的先天免疫。最近，有人提出 NADPH 氧化酶（NOX）同工酶在 Toll 样受体（TLR）介导的先天免疫反应中发挥功能作用。然而，TLR 和 NOX 介导的活性氧（ROS）产生之间的分子机制在人呼吸道黏膜中还了解甚少。
在这里，我们表明鞭毛蛋白诱导的 ROS 生成依赖于双氧化酶 2（DUOX2）的激活，这是由原代正常人鼻上皮（NHNE）细胞中[Ca2+]（i）动员调节的。有趣的是，我们观察到在 NHNE 细胞和 Duox2 敲除小鼠的鼻上皮中沉默 DUOX2 表达，在受到鞭毛蛋白刺激时，不能触发粘蛋白和 MIP-2？的产生。
我们在这项研究中的观察表明，鞭毛蛋白诱导的过氧化氢（H2O2）生成对于 TLR5 依赖性先天免疫反应至关重要，包括鼻上皮中 IL-8 的产生和 MUC5AC 的表达。此外，鞭毛蛋白-TLR5 轴激活的 DUOX2 介导的 H2O2 生成可能成为气道传染病炎症的新治疗靶点。
综上所述，我们提出 DUOX2 在 TLR5 依赖性鼻气道上皮炎症反应中发挥关键作用。
