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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: NOX4 regulates macrophage apoptosis resistance to induce fibrotic progression.

Authors: Larson-Casey, Jennifer L; Gu, Linlin; Kang, Jungsoon; Dhyani, Ashish; Carter, A Brent

Published In J Biol Chem, (2021 Jul)

Abstract: Pulmonary fibrosis is a progressive lung disease often occurring secondary to environmental exposure. Asbestos exposure is an important environmental mediator of lung fibrosis and remains a significant cause of disease despite strict regulations to limit exposure. Lung macrophages play an integral role in the pathogenesis of fibrosis induced by asbestos (asbestosis), in part by generating reactive oxygen species (ROS) and promoting resistance to apoptosis. However, the mechanism by which macrophages acquire apoptosis resistance is not known. Here, we confirm that macrophages isolated from asbestosis subjects are resistant to apoptosis and show they are associated with enhanced mitochondrial content of NADPH oxidase 4 (NOX4), which generates mitochondrial ROS generation. Similar results were seen in chrysotile-exposed WT mice, while macrophages from Nox4-/- mice showed increased apoptosis. NOX4 regulated apoptosis resistance by activating Akt1-mediated Bcl-2-associated death phosphorylation. Demonstrating the importance of NOX4-mediated apoptosis resistance in fibrotic remodeling, mice harboring a conditional deletion of Nox4 in monocyte-derived macrophages exhibited increased apoptosis and were protected from pulmonary fibrosis. Moreover, resolution occurred when Nox4 was deleted in monocyte-derived macrophages in mice with established fibrosis. These observations suggest that NOX4 regulates apoptosis resistance in monocyte-derived macrophages and contributes to the pathogenesis of pulmonary fibrosis. Targeting NOX4-mediated apoptosis resistance in monocyte-derived macrophages may provide a novel therapeutic target to protect against the development and/or progression of pulmonary fibrosis.

PubMed ID: 34023385 Exiting the NIEHS site

MeSH Terms: Animals; Apoptosis*; Cell Line; Disease Progression*; Female; Idiopathic Pulmonary Fibrosis/enzymology*; Idiopathic Pulmonary Fibrosis/pathology*; Lung/pathology; Macrophages/enzymology*; Macrophages/pathology*; Male; Mice, Inbred C57BL; Mitochondria/metabolism; Models, Biological; Monocytes/metabolism; NADPH Oxidase 4/metabolism*; Phosphorylation; Reactive Oxygen Species/metabolism; bcl-Associated Death Protein/metabolism

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Last Reviewed: December 05, 2024