title: Silver nanoparticles reduce brain inflammation and related neurotoxicity through induction of H2S-synthesizing enzymes.
abstract: Silver nanoparticles (AgNP) are known to penetrate into the brain and cause neuronal death. However, there is a paucity in studies examining the effect of AgNP on the resident immune cells of the brain, microglia. Given microglia are implicated in neurodegenerative disorders such as Parkinson's disease (PD), it is important to examine how AgNPs affect microglial inflammation to fully assess AgNP neurotoxicity. In addition, understanding AgNP processing by microglia will allow better prediction of their long term bioreactivity. In the present study, the in vitro uptake and intracellular transformation of citrate-capped AgNPs by microglia, as well as their effects on microglial inflammation and related neurotoxicity were examined. Analytical microscopy demonstrated internalization and dissolution of AgNPs within microglia and formation of non-reactive silver sulphide (Ag2S) on the surface of AgNPs. Furthermore, AgNP-treatment up-regulated microglial expression of the hydrogen sulphide (H2S)-synthesizing enzyme cystathionine-γ-lyase (CSE). In addition, AgNPs showed significant anti-inflammatory effects, reducing lipopolysaccharide (LPS)-stimulated ROS, nitric oxide and TNFα production, which translated into reduced microglial toxicity towards dopaminergic neurons. Hence, the present results indicate that intracellular Ag2S formation, resulting from CSE-mediated H2S production in microglia, sequesters Ag+ions released from AgNPs, significantly limiting their toxicity, concomitantly reducing microglial inflammation and related neurotoxicity.
authors.affiliation: Department of Materials and London Centre for Nanotechnology, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.|Parkinson's Disease Research Unit, Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Gonzalez-Carter
authors.affiliation: Department of Materials and London Centre for Nanotechnology, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.|Central Unit for Advanced Research Imaging, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Bey Fen
authors.initials: BF
authors.lastname: Leo
authors.affiliation: Department of Materials and London Centre for Nanotechnology, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.|National Heart and Lung Institute, Imperial College London, Guy Scadding Building, Cale Street, London, SW3 6LY, UK.
authors.forename: Pakatip
authors.initials: P
authors.lastname: Ruenraroengsak
authors.affiliation: Department of Materials and London Centre for Nanotechnology, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.
authors.forename: Shu
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Materials and London Centre for Nanotechnology, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.
authors.forename: Angela E
authors.initials: AE
authors.lastname: Goode
authors.affiliation: Department of Materials and London Centre for Nanotechnology, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.
authors.forename: Ioannis G
authors.initials: IG
authors.lastname: Theodorou
authors.affiliation: National Heart and Lung Institute, Imperial College London, Guy Scadding Building, Cale Street, London, SW3 6LY, UK.
authors.forename: Kian Fan
authors.initials: KF
authors.lastname: Chung
authors.affiliation: Electron Microscopy Science Technology Platform, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London, WC2A 3LY, UK.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Carzaniga
authors.affiliation: Department of Materials and London Centre for Nanotechnology, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.|Department of Chemistry and London Centre for Nanotechnology, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.
authors.forename: Milo S P
authors.initials: MS
authors.lastname: Shaffer
authors.affiliation: Parkinson's Disease Research Unit, Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK.
authors.forename: David T
authors.initials: DT
authors.lastname: Dexter
authors.affiliation: Department of Materials and London Centre for Nanotechnology, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.
authors.forename: Mary P
authors.initials: MP
authors.lastname: Ryan
authors.affiliation: Department of Materials and London Centre for Nanotechnology, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Porter
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003542:Cystathionine gamma-Lyase / Q000378:metabolism*; D004660:Encephalitis / Q000188:drug therapy / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006862:Hydrogen Sulfide / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D053768:Metal Nanoparticles / Q000737:chemistry*; D051379:Mice; D017628:Microglia / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012834:Silver / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008070:Lipopolysaccharides; D012834:Silver; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide