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

Abstract

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. 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. 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 <i>Ifng</i> expression and, at a later stage of disease, the promoted prevalence of proinflammatory macrophages that triggered severe intestinal inflammation. 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.