Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, and.
Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
JCI Insight. 2019 Aug 22;4(16):126551. doi: 10.1172/jci.insight.126551.
Macrophage activation is implicated in the development of pulmonary fibrosis by generation of profibrotic molecules. Although NADPH oxidase 4 (NOX4) is known to contribute to pulmonary fibrosis, its effects on macrophage activation and mitochondrial redox signaling are unclear. Here, we show that NOX4 is crucial for lung macrophage profibrotic polarization and fibrotic repair after asbestos exposure. NOX4 was elevated in lung macrophages from subjects with asbestosis, and mice harboring a deletion of NOX4 in lung macrophages were protected from asbestos-induced fibrosis. NOX4 promoted lung macrophage profibrotic polarization and increased production of profibrotic molecules that induce collagen deposition. Mechanistically, NOX4 further augmented mitochondrial ROS production and induced mitochondrial biogenesis. Targeting redox signaling and mitochondrial biogenesis prevented the profibrotic polarization of lung macrophages by reducing the production of profibrotic molecules. These observations provide evidence that macrophage NOX4 is a potentially novel therapeutic target to halt the development of asbestos-induced pulmonary fibrosis.
巨噬细胞的激活被认为与纤维化的发生有关，它可以产生促纤维化分子。虽然 NADPH 氧化酶 4（NOX4）已知与肺纤维化有关，但它对巨噬细胞激活和线粒体氧化还原信号的影响尚不清楚。在这里，我们发现 NOX4 对于石棉暴露后肺巨噬细胞的促纤维化极化和纤维化修复至关重要。在石棉肺患者的肺巨噬细胞中，NOX4 水平升高，而肺巨噬细胞中缺失 NOX4 的小鼠则能免受石棉诱导的纤维化。NOX4 促进肺巨噬细胞的促纤维化极化，并增加诱导胶原蛋白沉积的促纤维化分子的产生。在机制上，NOX4 进一步增加了线粒体 ROS 的产生，并诱导了线粒体生物发生。靶向氧化还原信号和线粒体生物发生通过减少促纤维化分子的产生来阻止肺巨噬细胞的促纤维化极化。这些观察结果为巨噬细胞 NOX4 是一个潜在的治疗靶点提供了证据，可用于阻止石棉诱导的肺纤维化的发展。
