TiO2 nanoparticles abrogate the protective effect of the Crohn's disease-associated variation within the PTPN22 gene locus

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Marlene Schwarzfischer - , University of Zurich (Author)
  • Anna Niechcial - , University of Zurich (Author)
  • Kristina Handler - , Swiss Federal Institute of Technology Zurich (Author)
  • Yasser Morsy - , University of Zurich (Author)
  • Marcin Wawrzyniak - , University of Zurich (Author)
  • Andrea S Laimbacher - , University of Zurich (Author)
  • Kirstin Atrott - , University of Zurich (Author)
  • Roberto Manzini - , University of Zurich (Author)
  • Katharina Baebler - , University of Zurich (Author)
  • Larissa Hering - , University of Zurich (Author)
  • Egle Katkeviciutė - , University of Zurich (Author)
  • Janine Häfliger - , University of Zurich (Author)
  • Silvia Lang - , University of Zurich (Author)
  • Maja E Keller - , University of Zurich (Author)
  • Jérôme Woodtli - , University of Zurich (Author)
  • Lisa Eisenbeiss - , University of Zurich (Author)
  • Thomas Kraemer - , University of Zurich (Author)
  • Elisabeth M Schraner - , University of Zurich (Author)
  • Mahesa Wiesendanger - , University of Zurich (Author)
  • Sebastian Zeissig - , Center for Regenerative Therapies Dresden, Department of internal Medicine I, Chair of Mucosal Immunology, University Hospital Carl Gustav Carus Dresden (Author)
  • Gerhard Rogler - , University of Zurich (Author)
  • Andreas E Moor - , Swiss Federal Institute of Technology Zurich (Author)
  • Michael Scharl - , University of Zurich (Author)
  • Marianne R Spalinger - , University of Zurich (Author)

Abstract

OBJECTIVE: Inflammatory bowel disease (IBD) is a multifactorial condition driven by genetic and environmental risk factors. A genetic variation in the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene has been associated with autoimmune disorders while protecting from the IBD subtype Crohn's disease. Mice expressing the murine orthologous PTPN22-R619W variant are protected from intestinal inflammation in the model of acute dextran sodium sulfate (DSS)-induced colitis. We previously identified food-grade titanium dioxide (TiO2, E171) as a neglected IBD risk factor. Here, we investigate the interplay of the PTPN22 variant and TiO2-mediated effects during IBD pathogenesis.

DESIGN: Acute DSS colitis was induced in wild-type and PTPN22 variant mice (PTPN22-R619W) and animals were treated with TiO2 nanoparticles during colitis induction. Disease-triggering mechanisms were investigated using bulk and single-cell RNA sequencing.

RESULTS: In mice, administration of TiO2 nanoparticles abrogated the protective effect of the variant, rendering PTPN22-R619W mice susceptible to DSS colitis. In early disease, cytotoxic CD8+ T-cells were found to be reduced in the lamina propria of PTPN22-R619W mice, an effect reversed by TiO2 administration. Normalisation of T-cell populations correlated with increased Ifng expression and, at a later stage of disease, the promoted prevalence of proinflammatory macrophages that triggered severe intestinal inflammation.

CONCLUSION: Our findings indicate that the consumption of TiO2 nanoparticles might have adverse effects on the gastrointestinal health of individuals carrying the PTPN22 variant. This demonstrates that environmental factors interact with genetic risk variants and can reverse a protective mechanism into a disease-promoting effect.

Details

Original languageEnglish
Article number325911
JournalGut
Volume2022
Publication statusPublished - 3 Oct 2022
Peer-reviewedYes

External IDs

Scopus 85142440972
Mendeley 020c77ec-2810-3326-88df-fb9f489c55c9
unpaywall 10.1136/gutjnl-2021-325911

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