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Silver Nanoparticle-Induced Autophagic-Lysosomal Disruption and NLRP3-Inflammasome Activation in HepG2 Cells Is Size-Dependent.
Toxicol Sci. 2016 Apr; 150(2):473-87.TS

Abstract

Silver nanoparticles (AgNPs) are incorporated into medical and consumer products to exploit their excellent antimicrobial properties; however, potential mechanisms of toxicity of AgNPs in mammalian cells are not fully understood. The objective of this study was to determine the mechanism of size- and concentration-dependent cytotoxicity of AgNPs in human liver-derived hepatoma (HepG2) cells. Mechanisms of toxicity were explored at subcytotoxic concentrations (≤10 µg/ml AgNPs) and autophagy induction, lysosomal activity, inflammasome-dependent caspase-1 activation, and apoptosis were examined. Using enhanced dark-field light microscopy, hyperspectral imaging, electron microscopy, and energy dispersive X-ray spectroscopy, AgNPs were shown to rapidly accumulate in cytoplasmic vesicles for up to 24 h and 10-nm AgNPs exhibited the highest uptake and accumulation. Autophagy and enhanced lysosomal activity were induced at noncytotoxic concentrations (1 µg/ml; primary particle size:10 > 50 >100 nm), whereas increased caspase-3 activity (associated with apoptosis) was observed at cytotoxic concentrations (10, 25, and 50 µg/ml). Subcytotoxic concentrations of AgNPs enhanced expression of LC3B, a pro-autophagic protein, and CHOP, an apoptosis inducing ER-stress protein, and activation of NLRP3-inflammasome (caspase-1, IL-1β). Disrupting the autophagy-lysosomal pathway through chloroquine or ATG5-siRNA exacerbated AgNPs-induced caspase-1 activation and lactate dehydrogenase release, suggesting that NLRP3-inflammasome plays an important role in AgNPs-induced cytotoxicity. Overall, 10-nm AgNPs showed the highest cellular responses compared with 50- and 100-nm AgNPs based on equal mass dosimetry. The results indicate the potential of vesicle-engulfed 10-nm AgNPs to induce cytotoxicity by a mechanism involving perturbations in the autophagy-lysosomal system and inflammasome activation.

Authors+Show Affiliations

Division of Biology, Chemistry, and Materials Science, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.Division of Biology, Chemistry, and Materials Science, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.Division of Biology, Chemistry, and Materials Science, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.Division of Biology, Chemistry, and Materials Science, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA Peter.Goering@fda.hhs.gov.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

26801583

Citation

Mishra, Anurag R., et al. "Silver Nanoparticle-Induced Autophagic-Lysosomal Disruption and NLRP3-Inflammasome Activation in HepG2 Cells Is Size-Dependent." Toxicological Sciences : an Official Journal of the Society of Toxicology, vol. 150, no. 2, 2016, pp. 473-87.
Mishra AR, Zheng J, Tang X, et al. Silver Nanoparticle-Induced Autophagic-Lysosomal Disruption and NLRP3-Inflammasome Activation in HepG2 Cells Is Size-Dependent. Toxicol Sci. 2016;150(2):473-87.
Mishra, A. R., Zheng, J., Tang, X., & Goering, P. L. (2016). Silver Nanoparticle-Induced Autophagic-Lysosomal Disruption and NLRP3-Inflammasome Activation in HepG2 Cells Is Size-Dependent. Toxicological Sciences : an Official Journal of the Society of Toxicology, 150(2), 473-87. https://doi.org/10.1093/toxsci/kfw011
Mishra AR, et al. Silver Nanoparticle-Induced Autophagic-Lysosomal Disruption and NLRP3-Inflammasome Activation in HepG2 Cells Is Size-Dependent. Toxicol Sci. 2016;150(2):473-87. PubMed PMID: 26801583.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Silver Nanoparticle-Induced Autophagic-Lysosomal Disruption and NLRP3-Inflammasome Activation in HepG2 Cells Is Size-Dependent. AU - Mishra,Anurag R, AU - Zheng,Jiwen, AU - Tang,Xing, AU - Goering,Peter L, Y1 - 2016/01/21/ PY - 2016/1/24/entrez PY - 2016/1/24/pubmed PY - 2016/12/28/medline KW - apoptosis KW - autophagy KW - caspase-1. KW - inflammasome KW - nanomaterials KW - silver nanoparticle SP - 473 EP - 87 JF - Toxicological sciences : an official journal of the Society of Toxicology JO - Toxicol Sci VL - 150 IS - 2 N2 - Silver nanoparticles (AgNPs) are incorporated into medical and consumer products to exploit their excellent antimicrobial properties; however, potential mechanisms of toxicity of AgNPs in mammalian cells are not fully understood. The objective of this study was to determine the mechanism of size- and concentration-dependent cytotoxicity of AgNPs in human liver-derived hepatoma (HepG2) cells. Mechanisms of toxicity were explored at subcytotoxic concentrations (≤10 µg/ml AgNPs) and autophagy induction, lysosomal activity, inflammasome-dependent caspase-1 activation, and apoptosis were examined. Using enhanced dark-field light microscopy, hyperspectral imaging, electron microscopy, and energy dispersive X-ray spectroscopy, AgNPs were shown to rapidly accumulate in cytoplasmic vesicles for up to 24 h and 10-nm AgNPs exhibited the highest uptake and accumulation. Autophagy and enhanced lysosomal activity were induced at noncytotoxic concentrations (1 µg/ml; primary particle size:10 > 50 >100 nm), whereas increased caspase-3 activity (associated with apoptosis) was observed at cytotoxic concentrations (10, 25, and 50 µg/ml). Subcytotoxic concentrations of AgNPs enhanced expression of LC3B, a pro-autophagic protein, and CHOP, an apoptosis inducing ER-stress protein, and activation of NLRP3-inflammasome (caspase-1, IL-1β). Disrupting the autophagy-lysosomal pathway through chloroquine or ATG5-siRNA exacerbated AgNPs-induced caspase-1 activation and lactate dehydrogenase release, suggesting that NLRP3-inflammasome plays an important role in AgNPs-induced cytotoxicity. Overall, 10-nm AgNPs showed the highest cellular responses compared with 50- and 100-nm AgNPs based on equal mass dosimetry. The results indicate the potential of vesicle-engulfed 10-nm AgNPs to induce cytotoxicity by a mechanism involving perturbations in the autophagy-lysosomal system and inflammasome activation. SN - 1096-0929 UR - https://www.unboundmedicine.com/medline/citation/26801583/Silver_Nanoparticle_Induced_Autophagic_Lysosomal_Disruption_and_NLRP3_Inflammasome_Activation_in_HepG2_Cells_Is_Size_Dependent_ DB - PRIME DP - Unbound Medicine ER -