Article Text
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.
- inflammatory bowel disease
- gastrointestinal immune response
- gut immunology
- IBD basic research
Data availability statement
Data are available in a public, open access repository. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article file or its supplementary material. RNAseq data are available at https://www.ncbi.nlm.nih.gov/bioproject/, Project ID PRJNA860794.
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Data availability statement
Data are available in a public, open access repository. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article file or its supplementary material. RNAseq data are available at https://www.ncbi.nlm.nih.gov/bioproject/, Project ID PRJNA860794.
Footnotes
Contributors MSchw: data acquisition, analysis, interpretation, drafting the manuscript. KH: processing and analysis of scRNAseq data. YM: processing and analysis of bulk RNAseq data. AN, MWa, KA, AL, RM, KB, LH, EK, JH, SL: data acquisition and analysis. MK, JW, LE, TK: ICP-MS and data analysis. EMS, MWi: electron microscopy and data interpretation. SZ, AM: study design. GR: study design and funding. MScha: conceived study, study design, supervision, data interpretation, funding and is the guarantor. MRS: study design, supervision, data interpretation.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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