title: TNFR1/phox interaction and TNFR1 mitochondrial translocation Thwart silica-induced pulmonary fibrosis.
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.
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219;
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Fazzi
authors.forename: Joel
authors.initials: J
authors.lastname: Njah
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Di Giuseppe
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Winnica
authors.forename: Kristina
authors.initials: K
authors.lastname: Go
authors.forename: Ernest
authors.initials: E
authors.lastname: Sala
authors.forename: Claudette M
authors.initials: CM
authors.lastname: St Croix
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Tyurin
authors.forename: Donald G
authors.initials: DG
authors.lastname: Phinney
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Fattman
authors.forename: George D
authors.initials: GD
authors.lastname: Leikauf
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.forename: Luis A
authors.initials: LA
authors.lastname: Ortiz
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D055370:Lung Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D012822:Silicon Dioxide / Q000009:adverse effects / Q000378:metabolism; D012829:Silicosis / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D047888:Receptors, Tumor Necrosis Factor, Type I; D012822:Silicon Dioxide; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1