Mechanisms linking ingested pollutants to increased incidence of allergy are poorly understood. We report that mice exposed to low doses of cadmium develop higher IgE responses following oral allergen sensitization and more severe allergic symptoms upon allergen challenge. The environmentally relevant doses of this pollutant also induced oxidative/inflammatory responses in the gut of SPF, but not germ-free mice. Interestingly, the increased IgE responses correlated with stimulation of the vitamin D3-metabolizing enzymes CYP27B1 and CYP24A1 in the gut and increased luminal levels of oxidized vitamin D3 metabolites that are not ligands of the vitamin D receptor. Inhibition of CYP27B1 and CYP24A1 via oral administration of pharmacological inhibitors reduced IgE responses induced in mice orally exposed to cadmium. Our findings identify local alteration of vitamin D signaling as a new mechanism for induction of IgE responses by environmental pollutants. They also identify vitamin D3-metabolizing enzymes as therapeutic targets for the treatment of allergy.
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This work was supported by NIH grants R01AI043197, R01DK101323, and R01AI145144, and the UL1TR001070 award from the National Center for Advancing Translational Sciences. The authors thank Arpad Somogyi and Matthew Bernier of the OSU Center for Clinical and Translational Science Mass Spectrometry & Proteomics Core for assistance with metabolomics and proteomics studies. The Mass Spectrometry & Proteomics Core was supported by NIH grant P30 CA016058 and the Fusion Orbitrap instrument was supported by NIH grant S10 OD018056.
The authors declare no competing interests.
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Kim, E., Bonnegarde-Bernard, A., Opiyo, S.O. et al. Pollutants enhance IgE sensitization in the gut via local alteration of vitamin D-metabolizing enzymes. Mucosal Immunol 15, 143–153 (2022). https://doi.org/10.1038/s41385-021-00440-4