Disruption of Sinonasal Epithelial Nrf2 Enhances Susceptibility to Rhinosinusitis in a Mouse Model
Editor's Note: This Manuscript was accepted for publication on June 8, 2020.
n.r.l. is a patent coinventor for methods treating vascular barrier dysfunction licensed to Navigen Pharmaceuticals, which is unrelated to this work. n.r.l. holds a small amount of stock in Navigen Pharmaceuticals, which is currently of no value.
Presented at the Triological Society Meeting at the Combined Otolaryngology Spring Meetings, National Harbor, Maryland, U.S.A., April 2018–28.
Accepted as a Triological Society Thesis and awarded the Edmund Prince Fowler Award.
This work was funded by grants from the National Institutes of Health (NIH ES020859, NIH R01AI143731, to m.r.).
Abstract
Objectives/Hypothesis
Oxidative stress has been postulated to play an important role in chronic rhinosinusitis. Nrf2 is a transcription factor that is involved in the regulation of multiple antioxidant genes, and its function has been previously shown to be important in sinonasal inflammation. Although the sinonasal implications of whole body Nrf2−/− has been reported, the function of sinonasal epithelial expression of Nrf2 has not been studied. The primary aim of this study was to generate a mouse model that is genetically deficient in epithelial-specific Nrf2 and to understand its role in regulating sinonasal inflammation.
Study Design
Basic science.
Methods
An epithelial-specific Nrf2 knockout mouse was generated by crossing Krt5-cre(K5) with Nrf2flox/flox. A papain-induced model of rhinosinusitis was performed in the resulting K5 Nrf2−/− mouse. Immunohistochemistry was performed to quantify goblet cell hyperplasia. Mucosal cellular infiltrates were quantified using flow cytometry, and tissue cytokines were measured using an enzyme-linked immunosorbent assay. Lastly, the cellular source of type 2 cytokines was determined using intracellular cytokine staining.
Results
Papain-sensitized mice lacking epithelial-specific Nrf2 demonstrate increased goblet cell hyperplasia, significant tissue eosinophilia, and statistically significant increase in mucosal IL-13 when compared to Nrf2 wild-type mice. Lastly, mucosal T cells were identified as the cellular source of IL-13.
Conclusions
We demonstrate enhanced severity of eosinophilic sinonasal inflammation from disruption of the epithelial-specific Nrf2 pathway. The responsiveness of Nrf2-directed antioxidant pathways may act as a major determinant of susceptibility to eosinophilic inflammation and may have potential as a therapeutic target for chronic rhinosinusitis.
Level of Evidence
NA Laryngoscope, 131:713–719, 2021
