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.

Targeting of Hepatic Macrophages by Therapeutic Nanoparticles

“…They produce oxidative stress that in turn modulates the autophagic process in the liver, disrupting liver metabolism and homeostasis (65). This hepatic oxidative damage has been reported in both in vitro and in vivo models for AuNPs, SiO 2 NPs, and AgNPs, with differences among the NP compositions (130)(131)(132)(133)(134). However, long-term effects need to be further characterized (65).…”

In Vivo Metabolic Response upon Exposure to Gold Nanorod Core/Silver Shell Nanostructures: Modulation of Inflammation and Upregulation of Dopamine

“…The observed changes in the above metabolites underlined that Au@Ag NRs resulted in different metabolic disruptions in mouse liver ( Table 2, 27 metabolite changes: 17 downregulated and 10 upregulated). Similarly, it is reported that Ag NPs can give rise to the decline in mitochondrial membrane potential, the impairment of lysosomal membrane, and even lactate dehydrogenase leakage [4,5,24,25]. Mitochondrial membrane potential is related with electron transport chain in mitochondrion, further reflecting the state of energy metabolism.…”

AgCuB nanoparticle eradicates intracellular S. aureus infection in bone cells: in vitro

“…AgCuB NPs were synthesized and characterized as discussed in [20]. Briefly, 0.1 M salt of silver nitrate, copper sulfate, and boric acid in a ratio of 70:20:10 respectively was mixed in ethylene glycol and after vigorous stirring, 10 mM each of L-cysteine and sodium hydroxide was added in a final volume of 20 ml which was added dropwise to the round bottom flask containing 10 mM of hydrazine hydrate and 10 mM of sodium citrate.…”

“…The boron has a lower atomic number, as a result, it cannot be detected by EDX spectroscopy; however, B was detected by inductively coupled plasma optical emission spectroscopy (ICP-OES)( Fig. 1H) [20].…”

“…Silver-copper-boron (AgCuB) have been studied as antimicrobial therapy in osteomyelitis animal model [19]. Exospore of AgCuB nanoparticles related immune response and its role in inflammation has been reported which depicted that an overdose can cause hepatotoxicity [20]. The in vitro study of AgCuB NP's toxicity in osteoblast cells and efficiency of antimicrobial activity at the intracellular level has not been reported.…”