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Updated: May 2, 2026
Establishing a Silicosis Rat Model via Exposure of Whole-Body to Respirable Silica
Published on: October 28, 2022
TNFR1/phox interaction and TNFR1 mitochondrial translocation Thwart silica-induced pulmonary fibrosis
Fabrizio Fazzi1, Joel Njah, Michelangelo Di Giuseppe
1Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219;
Abstract:
Macrophages play a fundamental role in innate immunity and the pathogenesis of silicosis. Phagocytosis of silica particles is associated with the generation of reactive oxygen species (ROS), secretion of cytokines, such as TNF, and cell death that contribute to silica-induced lung disease. In macrophages, ROS production is executed primarily by activation of the NADPH oxidase (Phox) and by generation of mitochondrial ROS (mtROS); however, the relative contribution is unclear, and the effects on macrophage function and fate are unknown. In this study, we used primary human and mouse macrophages (C57BL/6, BALB/c, and p47(phox-/-)) and macrophage cell lines (RAW 264.7 and IC21) to investigate the contribution of Phox and mtROS to silica-induced lung injury. We demonstrate that reduced p47(phox) expression in IC21 macrophages is linked to enhanced mtROS generation, cardiolipin oxidation, and accumulation of cardiolipin hydrolysis products, culminating in cell death. mtROS production is also observed in p47(phox-/-) macrophages, and p47(phox-/-) mice exhibit increased inflammation and fibrosis in the lung following silica exposure. Silica induces interaction between TNFR1 and Phox in RAW 264.7 macrophages. Moreover, TNFR1 expression in mitochondria decreased mtROS production and increased RAW 264.7 macrophage survival to silica. These results identify TNFR1/Phox interaction as a key event in the pathogenesis of silicosis that prevents mtROS formation and reduces macrophage apoptosis.
Insights
Reduced NADPH oxidase (Phox) activity in macrophages leads to increased mitochondrial ROS (mtROS), causing cell death in silicosis. TNFR1 interaction with Phox prevents mtROS, protecting macrophages and reducing lung injury.
Area of Science:
- Immunology
- Cell Biology
- Toxicology
Background:
- Macrophages are crucial in innate immunity and silicosis pathogenesis.
- Silica particle phagocytosis triggers reactive oxygen species (ROS) generation, cytokine release, and cell death, contributing to lung disease.
- ROS in macrophages are produced by NADPH oxidase (Phox) and mitochondrial ROS (mtROS), but their relative roles in silicosis are unclear.
Purpose of the Study:
- To investigate the distinct contributions of Phox and mtROS to silica-induced lung injury.
- To elucidate the mechanisms underlying macrophage dysfunction and apoptosis in silicosis.
- To identify molecular targets for mitigating silica-induced lung damage.
Main Methods:
- Utilized primary human and mouse macrophages (C57BL/6, BALB/c, p47(phox-/-)) and macrophage cell lines (RAW 264.7, IC21).
- Assessed ROS production (Phox and mtROS), cardiolipin oxidation, and cell death markers.
- Investigated the interaction between TNFR1 and Phox in macrophages.
- Analyzed lung inflammation and fibrosis in p47(phox-/-) mice following silica exposure.
Main Results:
- Reduced p47(phox) expression correlated with increased mtROS, cardiolipin oxidation, and cell death.
- p47(phox-/-) macrophages and mice showed elevated mtROS, inflammation, and fibrosis after silica exposure.
- Silica induced TNFR1 and Phox interaction in RAW 264.7 macrophages.
- Mitochondrial TNFR1 expression reduced mtROS and enhanced macrophage survival.
Conclusions:
- TNFR1/Phox interaction is a critical protective mechanism in silicosis pathogenesis.
- This interaction prevents excessive mtROS formation, thereby reducing macrophage apoptosis and mitigating lung injury.
- Targeting the TNFR1/Phox pathway may offer therapeutic strategies for silicosis.
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