Systemic Inhibition of NF-κB Activation Protects from Silicosis

Giuseppe, Michelangelo Di; Gambelli, Federica; Hoyle, Gary W.; Lungarella, Giuseppe; Studer, Sean M.; Richards, Thomas J.; Yousem, Sam; McCurry, Kenneth R.; Dauber, James H.; Kaminski, Naftali; Leikauf, George D.; Ortiz, Luis A.

doi:10.1371/journal.pone.0005689

Cited by 56 publications

(45 citation statements)

References 49 publications

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“…However, TNF makes an important contribution toward the survival of macrophages to silica. Previously, we found that inhibition of TNF-mediated NF-kB activation significantly enhanced silica-induced apoptosis in RAW 264.7 macrophages and worsened silica-induced lung injury in mice (1,27). The current work demonstrates that macrophages differ in their secretion of TNF in response to silica and that TNF expression in RAW 264.7 macrophages triggers TNFR1-signaling events that diminish ROS production.…”

Section: Discussionsupporting

confidence: 55%

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TNFR1/Phox Interaction and TNFR1 Mitochondrial Translocation Thwart Silica-Induced Pulmonary Fibrosis

Fazzi

Njah

Giuseppe

et al. 2014

The Journal of Immunology

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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 p47phox−/−) 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 p47phox 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 p47phox−/− macrophages, and p47phox−/− 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.

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Section: Discussionsupporting

confidence: 55%

“…Exposure to silica is common; .2 million people are exposed to silica in the United States every year, and silicosis remains a global threat for which no specific therapy is available (1).…”

mentioning

confidence: 99%

TNFR1/Phox Interaction and TNFR1 Mitochondrial Translocation Thwart Silica-Induced Pulmonary Fibrosis

Fazzi

Njah

Giuseppe

et al. 2014

The Journal of Immunology

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“…A similar connection has been described in a mouse model of experimental autoimmune thyroiditis where a reduction in TNF activity was associated with decreased fibrosis [43]. In separate studies, systemic inhibition of NFκB with BAY 11 in mouse models of silica-induced lung injury or liver injury induced by carbon tetrachloride resulted in reduced fibrosis [44, 45]. In addition, a link between TNF and TGF-β expression has been demonstrated in TIMP3 KO mice.…”

Section: Discussionmentioning

confidence: 58%

Loss of monocyte chemoattractant protein-1 alters macrophage polarization and reduces NFκB activation in the foreign body response

et al. 2015

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Implantation of biomaterials elicits a foreign body response characterized by fusion of macrophages to form foreign body giant cells and fibrotic encapsulation. Studies of macrophage polarization in this response have suggested that alternative (M2) activation is associated with more favorable outcomes. Here we investigated this process in vivo by implanting mixed cellulose ester filters or PDMS disks in the peritoneal cavity of WT and MCP-1 KO mice. We analyzed classical (M1) and alternative (M2) gene expression via Q-PCR, immunohistochemistry, and ELISA in both non-adherent cells isolated by lavage and implant-adherent cells. Our results show that macrophages undergo unique activation that displays features of both M1 and M2 polarization including induction of TNF, which induces the expression and nuclear translocation of p50 and RelA determined by immunofluorescence and western blot. Both processes were compromised in fusion-deficient MCP-1 KO macrophages in vitro and in vivo. Furthermore, inclusion of BAY 11-7028, an inhibitor of NFκB activation, reduced nuclear translocation of RelA and fusion in WT macrophages. Our studies suggest that peritoneal implants elicit a unique macrophage polarization phenotype leading to induction of TNF and activation of the NFκB pathway.

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“…This implied that blockade of the NFkB pathway might protect against lung fibrosis by decreasing YY1 expression. Interestingly, a recent report demonstrated that Bay11-7085 decreased silica-induced inflammation and collagen deposition (34), although potential effects of NF-kB inhibition on YY1 expression were not investigated in that report. Thus, in addition to promoting the expression of cytokines, chemokines, and other inflammatory mediators, these data suggest that by inducing YY1 expression, NF-kB promotes the expression of genes involved in tissue repair responses.…”

Section: Discussionmentioning

confidence: 93%

Yin Yang 1 Is a Novel Regulator of Pulmonary Fibrosis

Lin¹,

Sime²,

Xu³

et al. 2011

Am J Respir Crit Care Med

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Rationale: The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic pulmonary fibrosis (IPF). The transcription factor Yin Yang 1 (YY1) plays a role in the proliferation and differentiation of diverse cell types, but its role in fibrotic lung diseases is not known. Objectives: To elucidate the mechanism by which YY1 regulates fibroblast differentiation and lung fibrosis. Methods: Lung fibroblasts were cultured with transforming growth factor (TGF)-b or tumor necrosis factor-a. Nuclear factor (NF)-kB, YY1, and a-smooth muscle actin (SMA) were determined in protein, mRNA, and promoter reporter level. Lung fibroblasts and lung fibrosis were assessed in a partial YY1-deficient mouse and a YY1 f/f conditional knockout mouse after being exposed to silica or bleomycin. Measurements and Main Results: TGF-b and tumor necrosis factor-a up-regulated YY1 expression in lung fibroblasts. TGF-b-induced YY1 expression was dramatically decreased by an inhibitor of NF-kB, which blocked I-kB degradation. YY1 is significantly overexpressed in both human IPF and murine models of lung fibrosis, including in the aggregated pulmonary fibroblasts of fibrotic foci. Furthermore, the mechanism of fibrogenesis is that YY1 can up-regulate a-SMA expression in pulmonary fibroblasts. YY1-deficient (YY1 1/2 ) mice were significantly protected from lung fibrosis, which was associated with attenuated a-SMA and collagen expression. Finally, decreasing YY1 expression through instilled adenovirus-cre in floxed-YY1 f/f mice reduced lung fibrosis. Conclusions: YY1 is overexpressed in fibroblasts in both human IPF and murine models in a NF-kB-dependent manner, and YY1 regulates fibrogenesis at least in part by increasing a-SMA and collagen expression. Decreasing YY1 expression may provide a new therapeutic strategy for pulmonary fibrosis.

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Systemic Inhibition of NF-κB Activation Protects from Silicosis

Cited by 56 publications

References 49 publications

TNFR1/Phox Interaction and TNFR1 Mitochondrial Translocation Thwart Silica-Induced Pulmonary Fibrosis

TNFR1/Phox Interaction and TNFR1 Mitochondrial Translocation Thwart Silica-Induced Pulmonary Fibrosis

Loss of monocyte chemoattractant protein-1 alters macrophage polarization and reduces NFκB activation in the foreign body response

Yin Yang 1 Is a Novel Regulator of Pulmonary Fibrosis

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