Over the last several decades, there has been a striking increase in the incidence of food allergies and other Th2-mediated disorders, such as asthma, in the U.S. and other western countries. Although environmental factors are thought to play a significant role in this alarming trend, the specific causative agent(s) remain to be identified. We recently demonstrated that tert-butylhydroquinone (tBHQ), a food additive present in many processed foods, promotes polarization of T cells towards a Th2 lineage, a key step in the development of allergy. Furthermore, our preliminary studies demonstrate that tBHQ, at concentrations relevant to human exposure, exacerbates food allergy in an animal model, suggesting a potential role for tBHQ in the increased incidence of food allergy in humans. In further support of this, human exposure to tBHQ in food and food packaging has been increasing since 1972, which is coincident with the increased incidence of food allergy in humans. Our objective in this application is to determine the mechanism by which the synthetic food additive, tBHQ, promotes polarization of CD4 T cells towards a Th2 lineage. Our central hypothesis is that tBHQ drives Th2 polarization through activation of a feed-forward transcriptional program requiring Nrf2 and GATA-3 that exacerbates the anaphylactic response to food allergen. This hypothesis is based upon our previously published studies and strong preliminary data, which demonstrate that activation of the transcription factor, Nrf2, by tBHQ promotes Th2 differentiation as evidenced by increased production of the Th2 cytokines, IL-4, IL-5 and IL-13, and increased expression and DNA binding of the Th2 master regulator, GATA-3, in isolated CD4 T cells. Furthermore, our preliminary studies show that mice exposed to tBHQ in the diet, at concentrations present in human food, have increased IgE and IgG1 production and an exacerbated anaphylactic response in a mouse model of food allergy. We propose to test our central hypothesis by 1) determining the mechanism by which activation of Nrf2 by tBHQ promotes Th2 differentiation, 2) determining the mechanism by which Nrf2 is induced during Th2 differentiation and 3) elucidating the mechanism by which tBHQ increases IgE and IgG1 production and exacerbates clinical signs of anaphylaxis in a mouse model of food allergy. Our results have important implications for defining the effect of tBHQ and other Nrf2 activators on Th2 polarization and allergy. In addition, we expect to identify the mechanism by which tBHQ regulates T cell differentiation and exacerbates anaphylactic response to food allergen. This information will be vital to mitigate the rise in food allergy and should help identfy new targets for allergy therapy.

Public Health Relevance

Over the last several decades, there has been a striking increase in the incidence of food allergies in the U.S., but the underlying cause is unknown. Our studies demonstrate that the food additive, tBHQ, promotes immune responses to allergens, which exacerbates symptoms of food allergy. The purpose of this application is to determine the mechanism by which this occurs so that we are better equipped to identify chemicals, such as tBHQ, that promote allergy, and so we can discover new clinical targets in the treatment of allergy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES024966-01A1
Application #
9022630
Study Section
Special Emphasis Panel (ZES1)
Program Officer
Humble, Michael C
Project Start
2016-02-01
Project End
2021-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Michigan State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Zagorski, Joseph W; Turley, Alexandra E; Freeborn, Robert A et al. (2018) Differential effects of the Nrf2 activators tBHQ and CDDO-Im on the early events of T cell activation. Biochem Pharmacol 147:67-76
Boss, Allison P; Freeborn, Robert A; Duriancik, David M et al. (2018) The Nrf2 activator tBHQ inhibits the activation of primary murine natural killer cells. Food Chem Toxicol 121:231-236
Nault, Rance; Doskey, Claire M; Fader, Kelly A et al. (2018) Comparison of Hepatic NRF2 and Aryl Hydrocarbon Receptor Binding in 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Treated Mice Demonstrates NRF2-Independent PKM2 Induction. Mol Pharmacol 94:876-884
Zhang, Di; Rennhack, Jonathan; Andrechek, Eran R et al. (2018) Identification of an Unfavorable Immune Signature in Advanced Lung Tumors from Nrf2-Deficient Mice. Antioxid Redox Signal 29:1535-1552
VanDenBerg, Kelly R; Freeborn, Robert A; Liu, Sheng et al. (2017) Inhibition of early T cell cytokine production by arsenic trioxide occurs independently of Nrf2. PLoS One 12:e0185579
Haak, Andrew J; Appleton, Kathryn M; Lisabeth, Erika M et al. (2017) Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma. Mol Cancer Ther 16:193-204
Zagorski, Joseph W; Maser, Tyler P; Liby, Karen T et al. (2017) Nrf2-Dependent and -Independent Effects of tert-Butylhydroquinone, CDDO-Im, and H2O2 in Human Jurkat T Cells as Determined by CRISPR/Cas9 Gene Editing. J Pharmacol Exp Ther 361:259-267
Rockwell, Cheryl E; Turley, Alexandra E; Cheng, Xingguo et al. (2017) Persistent alterations in immune cell populations and function from a single dose of perfluorononanoic acid (PFNA) in C57Bl/6 mice. Food Chem Toxicol 100:24-33