NOX4 modulates macrophage phenotype and mitochondrial biogenesis in asbestosis

Our plain-English summary of NOX4 modulates macrophage phenotype and mitochondrial biogenesis in asbestosis, by C. He, J.L. Larson-Casey, D. Davis, et al (JCI Insight, 2019).

The study

• Authors: C. He, J.L. Larson-Casey, D. Davis, V.S. Hanumanthu, A.L.F. Longhini, V.J. Thannickal, L. Gu, A.B. Carter
• Journal: JCI Insight
• Published: 2019;4(16)
• Cited by: 46 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This laboratory study, from the University of Alabama at Birmingham, examined an enzyme called NOX4 in lung macrophages, which are immune cells in the lung. The authors compared macrophages taken from the lungs of people with asbestosis and of healthy volunteers, in small groups of 4 to 6 people each. They also placed chrysotile asbestos into the windpipes of mice, using man-made vitreous fibers as the comparison exposure. Mitochondrial NOX4 in macrophages from people with asbestosis was more than 3-fold that of healthy subjects. Two groups of mice were protected from asbestos-induced lung fibrosis: mice lacking NOX4 entirely, and mice with NOX4 deleted in cells of the granulocyte/monocyte lineage, which includes macrophages. In mice with normal NOX4, asbestos raised mitochondrial reactive oxygen species 10-fold in lung macrophages. After asbestos exposure, the lineage-deleted mice had nearly 3-fold less active TGF-β1, a scarring-related molecule, in fluid washed from their lungs than asbestos-exposed mice with intact NOX4. Cell experiments linked NOX4 to the production of new mitochondria. The authors concluded that macrophage NOX4 is a potentially novel therapeutic target to halt the development of asbestos-induced pulmonary fibrosis.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study with three parts: lung macrophages from human subjects with asbestosis and from normal volunteers, experiments in genetically modified mice exposed to asbestos, and cell-culture experiments
• Who was studied: Lung macrophages from normal subjects and from subjects with asbestosis, obtained at the University of Alabama at Birmingham. Groups were small, for example 5 and 5 for NOX4 mRNA, 4 and 4 for mitochondrial NOX4, and 6 and 6 for PGC-1α. The mice were wild-type mice, mice lacking NOX4 entirely, and mice with NOX4 deleted in cells of the granulocyte/monocyte lineage (Nox4–/–Lyz2-Cre), in groups of 3 to 7. The study also used mouse cell cultures. Study dates are not given.
• Exposure: Mice received 100 μg of chrysotile asbestos into the windpipe (intratracheally), compared with man-made vitreous fibers (MMVFs). Human asbestosis subjects had a strong history of asbestos exposure or pleural plaque on CT.
• Main results:
  • Mitochondrial NOX4 in lung macrophages from subjects with asbestosis was more than 3-fold that of normal subjects
  • Mice lacking NOX4 were protected from fibrosis after chrysotile exposure and had significantly less collagen than wild-type mice
  • Mice with NOX4 deleted in cells of the granulocyte/monocyte lineage (Nox4–/–Lyz2-Cre) were also protected from asbestos-induced pulmonary fibrosis
  • After asbestos exposure, Nox4–/–Lyz2-Cre mice had nearly 3-fold less active TGF-β1 in bronchoalveolar lavage fluid than asbestos-exposed control (Nox4fl/fl) mice
  • Subjects with asbestosis had more than 10-fold greater expression of pgc1a, a regulator of new mitochondria production, than normal subjects
  • In control (Nox4fl/fl) mice, asbestos produced 10-fold greater mitochondrial reactive oxygen species in lung macrophages. In Nox4–/–Lyz2-Cre mice, levels were reduced to the MMVF control level.
  • In cultured macrophages overexpressing NOX4, the compound Mdivi-1 reduced tgfb1 promoter activity to one-third of the level in vehicle-treated cells
• The authors' conclusion: The authors concluded that macrophage NOX4 is a potentially novel therapeutic target to halt the development of asbestos-induced pulmonary fibrosis.
• Limitations the authors state:
  • The authors state that they did not determine how monocyte-derived macrophages are recruited to the lung, and that this needs further investigation

Topics

The National Library of Medicine indexes this study under subjects our site covers: Asbestosis.

Medical terms in this study, explained in our Lexicon: Macrophage, Pulmonary Fibrosis, Asbestos Exposure, Fibrosis, Collagen, Deposition.

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• NOX4 regulates macrophage apoptosis resistance to induce fibrotic progression — J.L. Larson-Casey, L. Gu, et al. (2021)
• Cu,Zn-Superoxide Dismutase-Mediated Redox Regulation of Jumonji Domain Containing 3 Modulates Macrophage Polarization and Pulmonary Fibrosis — C. He, J.L. Larson-Casey, et al. (2016)
• Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization — L. Gu, J.L. Larson-Casey, et al. (2017)
• Alternative activation of macrophages and pulmonary fibrosis are modulated by scavenger receptor, macrophage receptor with collagenous structure — S. Murthy, J.L. Larson-Casey, et al. (2015)
• Asbestos and silica-induced changes in human alveolar macrophage phenotype — A. Holian, M.O. Uthman, et al. (1997)

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