Pro-inflammatory adjuvant properties of pigment-grade titanium dioxide particles are augmented by a genotype that potentiates interleukin 1β processing

BACKGROUND: Pigment-grade titanium dioxide (TiO(2)) particles are an additive to some foods (E171 on ingredients lists), toothpastes, and pharma−/nutraceuticals and are absorbed, to some extent, in the human intestinal tract. TiO(2) can act as a modest adjuvant in the secretion of the pro-inflammatory cytokine interleukin 1β (IL-1β) when triggered by common intestinal bacterial fragments, such as lipopolysaccharide (LPS) and/or peptidoglycan. Given the variance in human genotypes, which includes variance in genes related to IL-1β secretion, we investigated whether TiO(2) particles might, in fact, be more potent pro-inflammatory adjuvants in cells that are genetically susceptible to IL-1β-related inflammation. METHODS: We studied bone marrow-derived macrophages from mice with a mutation in the nucleotide-binding oligomerisation domain-containing 2 gene (Nod2 (m/m)), which exhibit heightened secretion of IL-1β in response to the peptidoglycan fragment muramyl dipeptide (MDP). To ensure relevance to human exposure, TiO(2) was food-grade anatase (119 ± 45 nm mean diameter ± standard deviation). We used a short ‘pulse and chase’ format: pulsing with LPS and chasing with TiO(2) +/− MDP or peptidoglycan. RESULTS: IL-1β secretion was not stimulated in LPS-pulsed bone marrow-derived macrophages, or by chasing with MDP, and only very modestly so by chasing with peptidoglycan. In all cases, however, IL-1β secretion was augmented by chasing with TiO(2) in a dose-dependent fashion (5–100 μg/mL). When co-administered with MDP or peptidoglycan, IL-1β secretion was further enhanced for the Nod2 (m/m) genotype. Tumour necrosis factor α was triggered by LPS priming, and more so for the Nod2 (m/m) genotype. This was enhanced by chasing with TiO(2), MDP, or peptidoglycan, but there was no additive effect between the bacterial fragments and TiO(2). CONCLUSION: Here, the doses of TiO(2) that augmented bacterial fragment-induced IL-1β secretion were relatively high. In vivo, however, selected intestinal cells appear to be loaded with TiO(2), so such high concentrations may be ‘exposure-relevant’ for localised regions of the intestine where both TiO(2) and bacterial fragment uptake occurs. Moreover, this effect is enhanced in cells from Nod2 (m/m) mice indicating that genotype can dictate inflammatory signalling in response to (nano)particle exposure. In vivo studies are now merited. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12989-017-0232-2) contains supplementary material, which is available to authorized users.