Size-Dependent Attenuation of TLR9 Signaling by Gold Nanoparticles in Macrophages

Abstract

Gold nanoparticles (GNPs), which are generally thought to be bio-inert and non-cytotoxic, have become one of the most ideal nanomaterials for medical applications. Once engulfed by phagocytes, the immunological effects of GNPs are still of concern and require detailed investigation. Therefore, this study explored the immunological significance of GNPs on TLR-mediated innate immunity in murine macrophages. GNP causes specific inhibition of TLR9 (CpG oligodeoxynucleotides; CpG-ODNs) signal in macrophages. The impaired CpG-ODN–induced TNF-α production is GNP concentration- and size-dependent in murine Raw264.7 cells: a GNP of 4 nm in size is more potent than a GNP of 11, 19, 35, or 45 nm in size. Consistent with cytokine inhibition, the CpG-ODN–induced phosphorylation of NF-κB and JNK as well as NF-κB activation are suppressed by GNPs. GNPs accumulate in lysosomes after phagocytosis and also increase TLR9-associated lysosomal cathepsin expression and activities, but this is irrelevant to TLR9 inhibition by GNPs in our studies. In addition, GNPs affected TLR9 translocation in response to CpG-ODNs and to phagosomes. Further exploring how GNPs inhibited TLR9 function, we found that GNPs could bind to high-mobility group box-1 (which is involved in the regulation of TLR9 signaling) inside the lysosomes. The current studies demonstrate that size-dependent inhibition of TLR9 function by GNP may be attributed to its binding to high-mobility group box-1.

Effect of oral administration of commercial gold nanocolloid on peripheral blood leukocytes in mice

“…Relatively numerous studies by other authors, completed on murine macrophages in vitro, confirm rapid scavenging of gold nanoparticles by cells (Shukla et al 2005, Yen et al 2009, Zhang et al 2011, Tsai et al 2012, Pissuwan et al 2013. Presumably, nanoparticles were also caught from the circulatory system by granulocytes and monocytes present in blood, whose activity was detected in this study.…”

“…However, results reported by various authors are highly divergent in this respect. Some have demonstrated the non-immunogenic character of gold nanoparticles or have even proven their anti-inflammatory effect, consisting of the inhibition of the production of reactive oxygen and nitrite species as well as pro-inflammatory cytokines in macrophages (Shukla et al 2005, Zhang et al 2011, Sumbayev et al 2012, Tsai et al 2012, Pissuwan et al 2013. Also, in vivo experiments conducted on several animal models of inflammatory conditions have confirmed the anti-inflammatory and antioxidant properties of gold nanoparticles, manifested by a decrease in levels of pro-inflammatory cytokines (IL-1β, TNF-α) and markers of oxidative tissue damage (Tsai et al 2007, Pedersen et al 2009, Dohnert et al 2012, Pereira et al 2012, Sumbayev et al 2012, Victor et al 2012.…”

Persistent Hepatic Structural Alterations Following Nanoceria Vascular Infusion in the Rat

“…While the mechanisms remain to be elucidated, the clinical presentation of metal fume fever appeared to be associated with lysosomal dissolution/releasing of zinc oxide nanoparticles (Kuschner et al 1995), localized release of nickel from a presumed insoluble compound playing a role in tumor formation (Pott et al 1992), and lysosomal-induced release of nickel ions with nuclear translocation in respiratory epithelial cells, all point to the pivotal role of the phagolysosome in nanoparticle metabolism and elimination (Goodman et al 2011). Other reports on lysosomal instability, phagolysosomal membrane breakage, and appearance of finer nanoparticles (Cho et al 2011;Miyawaki et al 2009;Rossi et al 2009;Tsai et al 2012) further indicate that the stability of the nanoparticle after phagolysosome enclosure is a major determinant of cellular toxicity. Absence of necrotic areas and a lack of fibrosis in the liver suggest that the continuous presence of nanoceria may be tolerated by the host.…”

The splenocyte proliferative response and cytokine secretion in mice after oral administration of commercial gold nanocolloid

“…Some of the available references confirm the suppression of macrophage functions in vitro by AuNPs. They retarded the response of human macrophages to IL-1β, and blocked the functions of TLR9 receptor in murine macrophages, decreasing the synthesis of TNF-α, IL-6 and IL-12p40 (Sumbayev et al 2012, Tsai et al 2012). In the in vivo studies, conducted on the animal models of inflammatory diseases, the suppression of macrophage functions by nanogold resulted in decreased levels of pro-inflammatory cytokines and protection from oxidative tissue damage (Tsai et al 2007, Pedersen et al 2009, Pereira et al 2012, Sumbayev et al 2012.…”

“…The nanoparticles uptake sometimes did not lead to any consequences, thus suggesting the lack of immunogenic effect (Shukla et al 2005, Zhang et al 2011, Pissuwan et al 2013. However, there are reports implicating the anti-inflammatory (Sumbayev et al 2012, Tsai et al 2012) as well as pro-inflammatory effect of ingested AuNPs (Yen et al 2009, Pissuwan et al 2013, which manifests itself by the inhibition or stimulation, respectively, of the synthesis of reactive oxygen or nitrite species and pro-inflammatory cytokines (IL-1, IL-6 and TNF-α). Notwithstanding that, for some time now, there have been colloidal solutions of gold nanoparticles available on the market, which are recommended in unconventional medicine for both external and internal use, e.g.…”