title: Acute systemic exposure to silver-based nanoparticles induces hepatotoxicity and NLRP3-dependent inflammation.
abstract: Nanoparticles (NPs) are increasingly being commercialized for use in biomedicine. NP toxicity following acute or chronic exposure has been described, but mechanistic insight into this process remains incomplete. Recent evidence from in vitro studies suggested a role for NLRP3 in NP cytotoxicity. In this study, we investigated the effect of systemic administration of composite inorganic NP, consisting of Ag:Cu:B (dose range 1-20 mg/kg), on the early acute (4-24 h post-exposure) and late phase response (96 h post-exposure) in normal and NLRP3-deficient mice. Our findings indicate that systemic exposure (≥2 mg/kg) was associated with acute liver injury due to preferential accumulation of NP in this organ and resulted in elevated AST, ALT and LDH levels. Moreover, within 24 h of NP administration, there was a dose-dependent increase in intraperitoneal neutrophil recruitment and upregulation in gene expression of several proinflammatory mediators, including TNF-α, IL-1β and S100A9. Histological analysis of liver tissue revealed evidence of dose-dependent hepatocyte necrosis, increase in sinusoidal Kupffer cells, lobular granulomas and foci of abscess formation which were most pronounced at 24 h following NP administration. NP deposition in the liver led to a significant upregulation in gene expression of S100A9, an endogenous danger signal recognition molecule of phagocytes, IL-1β and IL-6. The extent of proinflammatory cytokine activation and hepatotoxicity was significantly attenuated in mice deficient in the NLRP3 inflammasome, demonstrating the critical role of this innate immune system recognition receptor in the response to NP.
authors.affiliation: a Department of Medical Microbiology & Immunology , and.
authors.forename: Khalil B
authors.initials: KB
authors.lastname: Ramadi
authors.affiliation: a Department of Medical Microbiology & Immunology , and.
authors.forename: Yassir A
authors.initials: YA
authors.lastname: Mohamed
authors.affiliation: a Department of Medical Microbiology & Immunology , and.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Al-Sbiei
authors.affiliation: b Department of Pathology , United Arab Emirates University , Al Ain , United Arab Emirates .
authors.forename: Saeeda
authors.initials: S
authors.lastname: Almarzooqi
authors.affiliation: a Department of Medical Microbiology & Immunology , and.
authors.forename: Ghada
authors.initials: G
authors.lastname: Bashir
authors.affiliation: a Department of Medical Microbiology & Immunology , and.
authors.forename: Aisha
authors.initials: A
authors.lastname: Al Dhanhani
authors.affiliation: a Department of Medical Microbiology & Immunology , and.
authors.forename: Dhanya
authors.initials: D
authors.lastname: Sarawathiamma
authors.affiliation: c Department of Mechanical Engineering , College of Engineering, United Arab Emirates University , Al Ain , United Arab Emirates .
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Qadri
authors.affiliation: d Department of Internal Medicine and.
authors.forename: Javed
authors.initials: J
authors.lastname: Yasin
authors.affiliation: e Department of Physiology , United Arab Emirates University , Al Ain , United Arab Emirates , and.
authors.forename: Abderrahim
authors.initials: A
authors.lastname: Nemmar
authors.affiliation: f Department of Biochemistry , College of Medicine and Health Sciences, United Arab Emirates University , Al Ain , United Arab Emirates.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Fernandez-Cabezudo
authors.affiliation: c Department of Mechanical Engineering , College of Engineering, United Arab Emirates University , Al Ain , United Arab Emirates .
authors.forename: Yousef
authors.initials: Y
authors.lastname: Haik
authors.affiliation: a Department of Medical Microbiology & Immunology , and.
authors.forename: Basel K
authors.initials: BK
authors.lastname: Al-Ramadi
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000187:drug effects; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D007728:Kupffer Cells / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D053768:Metal Nanoparticles / Q000633:toxicity*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000172:deficiency* / Q000235:genetics; D010316:Particle Size; D012834:Silver / Q000493:pharmacokinetics / Q000633:toxicity*; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D012834:Silver
keywords: Acute nanotoxicity; IL-1β; NLRP3; S100A9; hepatotoxicity; silver nanoparticles