Silver Nanoparticles Induce Neutrophil Extracellular Traps Via Activation of PAD and Neutrophil Elastase

Abstract

Silver nanoparticles (AgNPs) are widely used in various fields because of their antimicrobial properties. However, many studies have reported that AgNPs can be harmful to both microorganisms and humans. Reactive oxygen species (ROS) are a key factor of cytotoxicity of AgNPs in mammalian cells and an important factor in the immune reaction of neutrophils. The immune reactions of neutrophils include the expulsion of webs of DNA surrounded by histones and granular proteins. These webs of DNA are termed neutrophil extracellular traps (NETs). NETs allow neutrophils to catch and destroy pathogens in extracellular spaces. In this study, we investigated how AgNPs stimulate neutrophils, specifically focusing on NETs. Freshly isolated human neutrophils were treated with 5 or 100 nm AgNPs. The 5 nm AgNPs induced NET formation, but the 100 nm AgNPs did not. Subsequently, we investigated the mechanism of AgNP-induced NETs using known inhibitors related to NET formation. AgNP-induced NETs were dependent on ROS, peptidyl arginine deiminase, and neutrophil elastase. The result in this study indicates that treatment of 5 nm AgNPs induce NET formation through histone citrullination by peptidyl arginine deiminase and histone cleavage by neutrophil elastase.

Modulation of the Functional State of Mouse Neutrophils by Selenium Nanoparticles In Vivo

“…However, many studies have reported that AgNPs can be harmful to both microorganisms and humans. The authors showed that 5 nm AgNPS caused NET release, but 100 nm AgNPs did not [ 14 ]. For SeNPs, the dependence of their efficiency on size was also shown [ 40 ].…”

“…In addition to the undeniable “positive” role of the neutrophil in the body, researchers have identified a range of pathological conditions, including autoimmunity and cancer, when neutrophil activity can be harmful to the body [ 11 , 12 ]. Thus, uncontrolled cytotoxic activity, excessive formation of ROS, and NETs can initiate tissue damage that can cause chronic inflammation and autoimmune disease [ 11 , 13 , 14 ].…”

PEGylation of Metal Oxide Nanoparticles Modulates Neutrophil Extracellular Trap Formation

“…Little is known about how nanomaterials impact NETosis, much less whether specifically metal oxide NPs and GBCAs enhance NETosis. How the physiochemical attributes of NPs modulate neutrophil behavior has been studied in gold, silver, and iron oxide NPs [ 76 , 77 , 78 , 79 , 80 ]. Manganese oxide NPs have not been studied specifically in regards to NETosis, but inhaled Mn 3 O 4 is known to cause respiratory inflammation; in fact, one study found that Mn 3 O 4 induced increases of oxidative stress in human alveolar macrophages of up to 700%, as well as more modest increases in oxidative stress in human airway epithelial cells [ 81 ].…”

“…The capacity of NPs to cause NETosis has also been investigated in silver NPs (AgNPs), particularly in the context of whether AgNP size or concentration influences NET formation [ 77 , 79 , 80 ]. Human neutrophils were exposed to 5 nm AgNPs and 100 nm AgNPs at varying concentrations of 0 µg/mL to 2 µg/mL for 4 h. Starting at a concentration of 1.2 µg/mL, the 5 nm AgNPs induced significant NETosis which increased with higher NP concentrations; however, the 100 nm AgNPs did not induce NETosis regardless of concentration [ 77 ]. Another study reported that 15 nm AgNPs induced neutrophil necrosis, increased oxidative stress, and facilitated the release of interleukin-1β, which itself can stimulate further NETosis and enhance neutrophil recruitment [ 79 , 80 , 84 ].…”

Health and Environmental Effect of Advanced Materials and Fine Particles

“…NETs allow neutrophils to catch and destroy pathogens in extracellular spaces. Kang et al [ 5 ] investigated how AgNPs stimulate neutrophils, specifically focusing on NETs. They found that AgNP induced NETs through ROS, peptidyl arginine deiminase, and neutrophil elastase.…”