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<p>Food-grade titanium dioxide (fgTiO<sub>2</sub>) is a bio-persistent particle under intense regulatory scrutiny. Yet paradoxically, the only known cell reservoirs for fgTiO<sub>2</sub> are graveyard intestinal pigment cells which are metabolically and immunologically quiescent. Here we identify immunocompetent cell targets of fgTiO<sub>2</sub> in humans, most notably in the subepithelial dome region of intestinal Peyer’s patches. Using multimodal microscopies with single-particle detection and per-cell / vesicle image analysis we achieve correlative dosimetry, quantitatively recapitulating human cellular exposures in the ileum of mice fed a fgTiO<sub>2</sub>-containing diet. Epithelial microfold cells selectively funnel fgTiO<sub>2</sub> into LysoMac and LysoDC cells with ensuing accumulation. Notwithstanding, proximity extension analyses for 92 protein targets reveal no measureable perturbation of cell signalling pathways. When chased with oral <i>ΔaroA</i>-<i>Salmonella</i>, pro-inflammatory signalling is confirmed, but no augmentation by fgTiO<sub>2</sub> is revealed despite marked same-cell loading. Interestingly, <i>Salmonella</i> causes the fgTiO<sub>2</sub>-recipient cells to migrate within the patch and, sporadically, to be identified in the lamina propria, thereby fully recreating the intestinal tissue distribution of fgTiO<sub>2</sub> in humans. Immunocompetent cells that accumulate fgTiO<sub>2</sub> in vivo are now identified and we demonstrate a mouse model that finally enables human-relevant risk assessments of ingested, bio-persistent (nano)particles.</p>

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Immunocompetent cell targeting by food-additive titanium dioxide

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月4日

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  • John W. Wills,
  • Alicja Dabrowska,
  • Jack Robertson,
  • Michelle Miniter,
  • Sebastian Riedle,
  • Huw D. Summers,
  • Rachel E. Hewitt,
  • Adeeba Fathima,
  • Alessandra Barreto da Silva,
  • Carlos A. P. Bastos,
  • Stuart Micklethwaite,
  • Åsa V. Keita,
  • Johan D. Söderholm,
  • Nicole C. Roy,
  • Don Otter,
  • Ravin Jugdaohsingh,
  • Pietro Mastroeni,
  • Andy P. Brown,
  • Paul Rees,
  • Jonathan J. Powell

摘要

Food-grade titanium dioxide (fgTiO2) is a bio-persistent particle under intense regulatory scrutiny. Yet paradoxically, the only known cell reservoirs for fgTiO2 are graveyard intestinal pigment cells which are metabolically and immunologically quiescent. Here we identify immunocompetent cell targets of fgTiO2 in humans, most notably in the subepithelial dome region of intestinal Peyer’s patches. Using multimodal microscopies with single-particle detection and per-cell / vesicle image analysis we achieve correlative dosimetry, quantitatively recapitulating human cellular exposures in the ileum of mice fed a fgTiO2-containing diet. Epithelial microfold cells selectively funnel fgTiO2 into LysoMac and LysoDC cells with ensuing accumulation. Notwithstanding, proximity extension analyses for 92 protein targets reveal no measureable perturbation of cell signalling pathways. When chased with oral ΔaroA-Salmonella, pro-inflammatory signalling is confirmed, but no augmentation by fgTiO2 is revealed despite marked same-cell loading. Interestingly, Salmonella causes the fgTiO2-recipient cells to migrate within the patch and, sporadically, to be identified in the lamina propria, thereby fully recreating the intestinal tissue distribution of fgTiO2 in humans. Immunocompetent cells that accumulate fgTiO2 in vivo are now identified and we demonstrate a mouse model that finally enables human-relevant risk assessments of ingested, bio-persistent (nano)particles.