Titanium dioxide nanoparticles exacerbate DSS-induced colitis: role of the NLRP3 inflammasome

Abstract

ObjectiveWestern lifestyle and diet are major environmental factors playing a role in the development of IBD. Titanium dioxide (TiO2) nanoparticles are widely used as food additives or in pharmaceutical formulations and are consumed by millions of people on a daily basis. We investigated the effects of TiO2 in the development of colitis and the role of the nucleotide-binding oligomerisation domain receptor, pyrin domain containing (NLRP)3 inflammasome.DesignWild-type and NLRP3-deficient mice with dextran sodium sulfate-induced colitis were orally administered with TiO2 nanoparticles. The proinflammatory effects of TiO2 particles in cultured human intestinal epithelial cells (IECs) and macrophages were also studied, as well as the ability of TiO2 crystals to traverse IEC monolayers and accumulate in the blood of patients with IBD using inductively coupled plasma mass spectrometry.ResultsOral administration of TiO2 nanoparticles worsened acute colitis through a mechanism involving the NLRP3 inflammasome. Importantly, crystals were found to accumulate in spleen of TiO2-administered mice. In vitro, TiO2 particles were taken up by IECs and macrophages and triggered NLRP3-ASC-caspase-1 assembly, caspase-1 cleavage and the release of NLRP3-associated interleukin (IL)-1β and IL-18. TiO2 also induced reactive oxygen species generation and increased epithelial permeability in IEC monolayers. Increased levels of titanium were found in blood of patients with UC having active disease.ConclusionThese findings indicate that individuals with a defective intestinal barrier function and pre-existing inflammatory condition, such as IBD, might be negatively impacted by the use of TiO2 nanoparticles.

The Search for Causative Environmental Factors in Inflammatory Bowel Disease

“…The total uptake of nanoparticles by patients is at an average of 2.5 mg per person and day but may increase up to 40 mg. Interestingly, there is a high content of titanium dioxide in coffee whitener, pastry (due to the flour content), toothpaste, chewing gum or drug preparations. We could demonstrate that titanium dioxide activates the immune system [91] . This activation is mainly mediated via a protein complex called the inflammasome.…”

“…The effector subunit is caspase-1 that cleaves prointerleukin 1β (IL-1β) and to the mature IL-1β and pro-IL-18 that can then be secreted. We found that in cell culture titanium dioxide was a strong activator of the inflammasome and subsequently induced IL-1β release [91] . In a mouse model, there was an aggravation of colitis induced by dextran sodium sulfate in the presence of titanium dioxide in the diet [91] .…”

“…In NALP3, this effect was absent in knockout mice that lack the receptor for inorganic nanoparticles [91] . Interestingly, in patients with active UC, we could measure increased titanium levels in the blood serum indicating that indeed in patients with active inflammation of the colon titanium dioxide is taken up into the body [91] . When it is taken up, it most likely also activates the inflammasome; however, we have not proven that directly in our manuscript.…”

“…In a recent publication, we could identify a potential mechanism by which diet-derived nanoparticles can induce inflammasome activation and therefore contribute to intestinal inflammation [91] . One of those nanoparticles frequently used in the food industry is titanium dioxide, usually used as microparticles.…”

Review: the potential impact of surface crystalline states of titanium for biomedical applications

“…As a result of NF-κB activation, macrophages start to secrete a panel of pro-inflammatory cytokines (TNFα, IL-1β, IL-6, IL-8, shown that phagocytosis of titanium nano-and microparticles up-regulates the expression of TNFα, IL-1β and IL-6 on both mRNA and protein levels (Beidelschies et al, 2008, Luo et al, 2016, Minematsu et al, 2007, Naganuma et al, 2016, Pajarinen et al, 2013, Rakshit et al, 2006, Ruiz et al, 2016, Valles et al, 2006, Yazdi et al, 2010. Additionally, the inflammasome protein NLPR3 which is responsible for IL-1β and IL-18 activation (Martinon et al, 2002), is also up-regulated in macrophages by titanium (Naganuma et al, 2016, Ruiz et al, 2016, Yazdi et al, 2010.…”