Effect of TiO₂Nanoparticles on Inflammasome-Mediated Airway Inflammation and Responsiveness

Abstract

PurposeNanoparticles (NPs) may cause cell and tissue damage, leading to local and systemic inflammatory responses and adverse effects on health due to the inhalation of particulate matter. The inflammasome is a major regulator of inflammation through its activation of pro-caspase-1, which cleaves pro-interleukin-1β (pro-IL-1β) into its mature form and may induce acute and chronic immune responses to NPs. However, little is known about the response of the inflammasome to NP exposure via the airways in asthma. The aim of this study was to identify the impact of titanium dioxide (TiO2) NPs on inflammasome in a mouse model of allergic asthma.MethodsMice were treated with ovalbumin (OVA) or TiO2 NPs. IL-1β, IL-18, NAIP, CIITA, HET-E, TP-2 (NACHT), leucine-rich repeat (LRR), pyrin domain-containing protein 3 (NLRP3), and caspase-1 were assessed by Western blotting. Caspase-1 was assessed by immunohistochemistry (IHC). Levels of reactive oxygen species (ROS)—as markers of oxidative damage—and the mediators 8-isoprostane and carbonyl were measured by enzyme-linked immunosorbent assay (ELISA).ResultsAirway hyperresponsiveness (AHR) and inflammation were increased in OVA-sensitized/challenged mice, and these responses were exacerbated by exposure to TiO2 NPs. NP treatment increased IL-1β and IL-18 expression in OVA-sensitized/challenged mice. NPs augmented the expression of NLRP3 and caspase-1, leading to production of active caspase-1 in the lung. Caspase-1 expression was increased and exacerbated by TiO2 NP exposure in OVA-sensitized/challenged mice. ROS levels tended to be increased in OVA-sensitized/challenged and OVA-sensitized/challenged-plus-TiO2 NP-exposed mice.ConclusionsOur data demonstrated that inflammasome activation occured in asthmatic lungs following NP exposure, suggesting that targeting the inflammasome may assist in controling NP-induced airway inflammation and hyperresponsiveness.

<p>NLRP3 inflammasome, oxidative stress, and apoptosis induced in the intestine and liver of rats treated with titanium dioxide nanoparticles: in vivo and in vitro study</p>

“…[10][11][12] It has also been shown that TiO 2 NPs increase ROS, inflammation, and apoptosis in the respiratory system. 13 ROS attacks biomolecules such as DNA, proteins, lipids, and carbohydrates, which cause oxidation, methylation, deamination, apoptosis, and, consequently, lead to cell death. 14 Azim et al 7 showed that oral administration of TiO 2 NPs (150 mg/kg/day) for 2 weeks in mice markedly elevated liver enzymes, malondialdehyde (MDA) levels, and gene expressions of NF-κB and Bax in hepatic tissue.…”

Submicron Crystals of the Parkinson’s Disease Substantia nigra: Calcium Oxalate, Titanium Dioxide and Iron Oxide

“…Both COD and TiO2 are phagocytized and NLRP3 inflammasome activating. [20,24,25,38,[41][42][43][44][45][46][47] If they activate also the microglial NLRP3 inflammasome, as is likely, proximal dopaminergic neurons would die. Because the number of microglia approaches the number of neuronal cells of the brain [65] each dopaminergic cell has on the average more than one proximal microglial cell.…”

“…In animals inhaling the pigment, TiO2 particles were detected also in the brain. [61] Although the TiO2 particles are phagocytized and activate the NLRP3 inflammasome [20,41,47,79,80] their human pathogenicity is less well established than that of the COD particles. [37,69,81] Nevertheless, treatment of dopaminergic neurons with TiO2 has been shown to increase α-synuclein expression and to cause its aggregation in a dose-dependent manner.…”

“…[40] Both activate the NLRP3 inflammasome. [24,25,38,[41][42][43][44][45][46][47] Crystalline COD is associated with human lesions [31,33,34,[48][49][50] and has been reported in the human brain, [51] particularly when patients are lethally poisoned by the antifreeze ethylene glycol. [52][53][54] Ethylene glycol is metabolized to oxalic acid [55,56] and is precipitated in the brain as calcium oxalate [57].…”

The Toxicology of Engineered Nanomaterials in Asthma

“…Increases in the T H 2 cytokines IL-4, IL-13 and IL-5 were seen, and Mishra et al found elevated Socs3 expression, which is associated with airway inflammation, in TiO 2 exposed mice which was NF-κB-dependent [18]. TiO 2 NPs also increase levels of caspase-1 and activate the NLRP3 inflammasome to generate increased production of pro-inflammatory IL-1β, likely through reactive oxygen species (ROS) production [16]. Genetic susceptibility has also been shown to affect the immune response in the OVA model; Gustafsson et al found differences in TiO 2 -induced inflammation in two susceptible rat strains, with both showing exacerbated IgE production and neutrophilia [19].…”