Silica nanoparticles inhibit the cation channel TRPV4 in airway epithelial cells

Abstract

BackgroundSilica nanoparticles (SiNPs) have numerous beneficial properties and are extensively used in cosmetics and food industries as anti-caking, densifying and hydrophobic agents. However, the increasing exposure levels experienced by the general population and the ability of SiNPs to penetrate cells and tissues have raised concerns about possible toxic effects of this material. Although SiNPs are known to affect the function of the airway epithelium, the molecular targets of these particles remain largely unknown. Given that SiNPs interact with the plasma membrane of epithelial cells we hypothesized that they may affect the function of Transient Receptor Potential Vanilloid 4 (TRPV4), a cation-permeable channel that regulates epithelial barrier function. The main aims of this study were to evaluate the effects of SiNPs on the activation of TRPV4 and to determine whether these alter the positive modulatory action of this channel on the ciliary beat frequency in airway epithelial cells.ResultsUsing fluorometric measurements of intracellular Ca2+ concentration ([Ca2+]i) we found that SiNPs inhibit activation of TRPV4 by the synthetic agonist GSK1016790A in cultured human airway epithelial cells 16HBE and in primary cultured mouse tracheobronchial epithelial cells. Inhibition of TRPV4 by SiNPs was confirmed in intracellular Ca2+ imaging and whole-cell patch-clamp experiments performed in HEK293T cells over-expressing this channel. In addition to these effects, SiNPs were found to induce a significant increase in basal [Ca2+]i, but in a TRPV4-independent manner. SiNPs enhanced the activation of the capsaicin receptor TRPV1, demonstrating that these particles have a specific inhibitory action on TRPV4 activation. Finally, we found that SiNPs abrogate the increase in ciliary beat frequency induced by TRPV4 activation in mouse airway epithelial cells.ConclusionsOur results show that SiNPs inhibit TRPV4 activation, and that this effect may impair the positive modulatory action of the stimulation of this channel on the ciliary function in airway epithelial cells. These findings unveil the cation channel TRPV4 as a primary molecular target of SiNPs.

Crystalline silica particles cause rapid NLRP3-dependent mitochondrial depolarization and DNA damage in airway epithelial cells

“…These data indicate that silica induces NLRP3 inflammasome activation within 10 min. A similar, perhaps related, short time span has been shown for effects on Ca 2+ levels and for the inhibition of the cation channel TRPV4 induced by silica nanoparticles in 16HBE cells [18].…”

Calcium-dependent cyto- and genotoxicity of nickel metal and nickel oxide nanoparticles in human lung cells

“…Another receptor that could potentially be involved is TRPV4, a Ca 2+ permeable non-selective cation channel that acts as a regulator of both microtubules and actin [ 54 ]. Interestingly, silica NPs were recently shown to inhibit TRPV4 activation in cultured human airway epithelial cells 16HBE [ 55 ]. Taken together, the involvement of plasma membrane receptors versus intracellular effects in relation to the effects of Ni and NiO NPs, as well as Ni ionic species, need to be explored further.…”

Mechanisms of ultrafine particle-induced respiratory health effects

“…P2X7 receptors, which play a role in neuroinflammation, are frequently coexpressed with another P2X receptor, P2X4 89 . Silica nanoparticles inhibit TRPV4 activation and impair the positive modulatory action of TRPV4 channel stimulation on the frequency of ciliary beating in airway epithelial cells 90 . The P2X7 receptor is involved in inflammation triggered by SiO 2 and TiO 2 UFPs by increasing IL-1β secretion, likely through the inflammasome pathway 91 .…”