Phagolysosome acidification is required for silica and engineered nanoparticle-induced lysosome membrane permeabilization and resultant NLRP3 inflammasome activity

Jessop, Forrest; Hamilton, Raymond F.; Rhoderick, Joseph F.; Fletcher, Paige; Holian, Andrij

doi:10.1016/j.taap.2017.01.012

Cited by 71 publications

(62 citation statements)

References 57 publications

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“…By holding the tongue to the side, the solution was aspirated into the lungs. This silica concentration was selected because we have shown that it leads to inflammation and fibrosis in mice in our previous studies [ 31 , 32 , 57 ].…”

Section: Methodsmentioning

confidence: 99%

Imipramine blocks acute silicosis in a mouse model

et al. 2017

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BackgroundInhalation of crystalline silica is associated with pulmonary inflammation and silicosis. Although silicosis remains a prevalent health problem throughout the world, effective treatment choices are limited. Imipramine (IMP) is a FDA approved tricyclic antidepressant drug with lysosomotropic characteristics. The aim of this study was to evaluate the potential for IMP to reduce silicosis and block phagolysosome membrane permeabilization.MethodsC57BL/6 alveolar macrophages (AM) exposed to crystalline silica ± IMP in vitro were assessed for IL-1β release, cytotoxicity, particle uptake, lysosomal stability, and acid sphingomyelinase activity. Short term (24 h) in vivo studies in mice instilled with silica (± IMP) evaluated inflammation and cytokine release, in addition to cytokine release from ex vivo cultured AM. Long term (six to ten weeks) in vivo studies in mice instilled with silica (± IMP) evaluated histopathology, lung damage, and hydroxyproline content as an indicator of collagen accumulation.ResultsIMP significantly attenuated silica-induced cytotoxicity and release of mature IL-1β from AM in vitro. IMP treatment in vivo reduced silica-induced inflammation in a short-term model. Furthermore, IMP was effective in blocking silica-induced lung damage and collagen deposition in a long-term model. The mechanism by which IMP reduces inflammation was explored by assessing cellular processes such as particle uptake and acid sphingomyelinase activity.ConclusionsTaken together, IMP was anti-inflammatory against silica exposure in vitro and in vivo. The results were consistent with IMP blocking silica-induced phagolysosomal lysis, thereby preventing cell death and IL-1β release. Thus, IMP could be therapeutic for silica-induced inflammation and subsequent disease progression as well as other diseases involving phagolysosomal lysis.Electronic supplementary materialThe online version of this article (10.1186/s12989-017-0217-1) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Imipramine blocks acute silicosis in a mouse model

et al. 2017

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“…Activation of NLRP3 by environmental irritants such as silica, 58 asbestos 58 and alum 61 has been authenticated. 62 Furthermore, structure-varied nanoparticles such as monosodium urate, 63 nano-SiO 2 , 58 black carbon 64 and carbon nanotubes 65 are able to actuate NLRP3 inflammasome. NLRP3 activation induced by QDs was first reported in hepatic cells and the liver of mice.…”

Section: Pyroptosismentioning

confidence: 99%

“…Moreover, cathepsin plays an indispensable role in this process. 62 It has been reported that nano-silver 52 and nano-rare earth metal oxide 53 have the capability to stimulate inflammasome activation due to disruption of lysosomal homeostasis. In addition, lysosomal damage induced by nanomaterials is closely related to the characteristics of nanoparticles.…”

Section: Lysosomal Rupturementioning

confidence: 99%

Dysfunction of various organelles provokes multiple cell death after quantum dot exposure

Wang

Tang

2018

IJN

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Quantum dots (QDs) are different from the materials with the micrometer scale. Owing to the superiority in fluorescence and optical stability, QDs act as possible diagnostic and therapeutic tools for application in biomedical field. However, potential threats of QDs to human health hamper their wide utilization in life sciences. It has been reported that oxidative stress and inflammation are involved in toxicity caused by QDs. Recently, accumulating research unveiled that disturbance of subcellular structures plays a magnificent role in cytotoxicity of QDs. Diverse organelles would collapse during QD treatment, including DNA damage, endoplasmic reticulum stress, mitochondrial dysfunction and lysosomal rupture. Different forms of cellular end points on the basis of recent research have been concluded. Apart from apoptosis and autophagy, a new form of cell death termed pyroptosis, which is finely orchestrated by inflammasome complex and gasdermin family with secretion of interleukin-1 beta and interleukin-18, was also summarized. Finally, several potential cellular signaling pathways were also listed. Activation of Toll-like receptor-4/myeloid differentiation primary response 88, nuclear factor kappa-light-chain-enhancer of activated B cells and NACHT, LRR and PYD domains-containing protein 3 inflammasome pathways by QD exposure is associated with regulation of cellular processes. With the development of QDs, toxicity evaluation is far behind its development, where specific mechanisms of toxic effects are not clearly defined. Further studies concerned with this promising area are urgently required.

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“…Inhaled silica dust disrupted lysosomes, which released lysosomal cathepsins (Cats) and other hydrolases into the cytosol [ 31 ]. In this study, we confirmed Cat D, S, H, L and PSAP were significantly upregulated in the lung of silica-exposed rats.…”

Section: Discussionmentioning

confidence: 99%

Comparative proteomic analysis of silica-induced pulmonary fibrosis in rats based on tandem mass tag (TMT) quantitation technology

Geng

Zhang

et al. 2020

PLoS ONE

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Silicosis is a systemic disease characterized by chronic persistent inflammation and incurable pulmonary fibrosis with the underlying molecular mechanisms to be fully elucidated. In this study, we employed tandem mass tag (TMT) based on quantitative proteomics technology to detect differentially expressed proteins (DEPs) in lung tissues of silica-exposed rats. A total of 285 DEPs (145 upregulated and 140 downregulated) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the biological pathway and functional classification of the proteins. Results showed that these DEPs were mainly enriched in the phagosome, lysosome function, complement and the coagulation cascade, glutathione metabolism, focal adhesion and ECM-receptor interactions. To validate the proteomics data, we selected and analyzed the expression trends of six proteins including CD14, PSAP, GM2A, COL1A1, ITGA8 and CLDN5 using parallel reaction monitoring (PRM). The consistent result between PRM and TMT indicated the reliability of our proteomic data. These findings will help to reveal the pathogenesis of silicosis and provide potential therapeutic targets. Data are available via ProteomeXchange with identifier PXD020625 .

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Phagolysosome acidification is required for silica and engineered nanoparticle-induced lysosome membrane permeabilization and resultant NLRP3 inflammasome activity

Cited by 71 publications

References 57 publications

Imipramine blocks acute silicosis in a mouse model

Imipramine blocks acute silicosis in a mouse model

Dysfunction of various organelles provokes multiple cell death after quantum dot exposure

Comparative proteomic analysis of silica-induced pulmonary fibrosis in rats based on tandem mass tag (TMT) quantitation technology

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