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

Abstract

Objective: Western 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.

Design: Wild-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.

Results: Oral 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.

Conclusion: These 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.

Keywords: IMMUNE RESPONSE; INFLAMMATORY BOWEL DISEASE; INFLAMMATORY MECHANISMS; INTESTINAL BARRIER FUNCTION; REACTIVE OXYGEN SPECIES.