Cell Targeting and Adjuvant Activity of Dietary Titanium Dioxide

Abstract

ABSTRACTFood-grade titanium dioxide (fgTiO2) is a bio-persistent particle under intense regulatory scrutiny. Paradoxically, meaningfulin vivocellular accumulation has never been demonstrated: the only known cell targets for fgTiO2are ‘graveyard’ intestinal pigment cells which are metabolically and immunologically quiescent. Here, we identify major new immunocompetent cell reservoirs of fgTiO2in humans, most notably in the subepithelial dome region of intestinal Peyer’s patches. Using multimodal microscopy techniques with single-particle detection and per-cell / vesicle image analysis we achieved correlative dosimetry, quantitatively recapitulating human cellular exposures in a mouse model. Epithelial microfold cells specifically funneled fgTiO2into LysoMac and LysoDC cells, which co-accumulated attenuated ΔaroA-Salmonellaupon sequential oral challenge. By proximity extension analyses, a clearSalmonellaeffect on pro-inflammatory signalling was confirmed, but no interaction with fgTiO2was revealed for 92 protein targets despite marked same-cell accumulation. In contrast,Salmonellacaused the fgTiO2-recipient cells to migrate towards the follicle margins and, sporadically, to the lamina propria recreating the human intestinal tissue distribution of fgTiO2. Physiologically active cell targets that accumulate fgTiO2are now identified. fgTiO2appears neither a danger signal nor an adjuvant in wild-type genotypes and we demonstrate a mouse model that finally enables human-relevant risk assessments of ingested (nano)particles.