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Pollutants enhance IgE sensitization in the gut via local alteration of vitamin D-metabolizing enzymes

Abstract

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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Fig. 1: Prior chronic ingestion of subtoxic doses of Cd enhances IgE responses and allergy severity.
Fig. 2: Chronic ingestion of subtoxic doses of Cd induces oxidative stress and inflammatory responses.
Fig. 3: IgE-promoting effects of low doses of Cd are lost in the absence of gut microbiota.
Fig. 4: Chronic ingestion of subtoxic doses of Cd alters the gut microbiome, and luminal metabolite and proteomic profiles.
Fig. 5: Cd-induced gut microenvironment enhances IgE responses via stimulation of PGE2.
Fig. 6: Vitamin D3-metabolizing enzymes and oxidized vitamin D3 metabolites regulate IgE production in mice exposed to Cd.
Fig. 7: Mechanisms of enhanced IgE sensitization by ingested cadmium.

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Acknowledgements

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.

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E.K. conducted the experiments, analyzed the data, and wrote the manuscript. A.B., M.R.J., and Z.A. conducted the experiments and analyzed the data. S.O. performed the statistical analyses. B.H.A. designed the experiments and reviewed the manuscript. E.C. designed the experiments, analyzed the data, and reviewed the manuscript. P.N.B. designed the experiments, analyzed the data, and wrote the manuscript. Current address for AB: Zoetis, Louvain-la-Neuve, Belgium. Current address for ZA: Nationwide Children Hospital, Columbus, Ohio.

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Correspondence to Prosper N. Boyaka.

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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

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