Induction of airway allergic inflammation by hypothiocyanite via epithelial cells

Hypothiocyanite (OSCN^-) serves as a potent innate defense system against microbes in the lungs. OSCN^- is generated by the catalysis of peroxidases using thiocyanate transported via several anion transporters, including pendrin/SLC26A4 and hydrogen peroxide (H₂O₂) generated by Duox1 and Duox2. We previously demonstrated that expression of pendrin, peroxidases, and Duox1/Duox2 is up-regulated in bronchial asthma patients and/or asthma model mice and that these molecules are important in accelerating airway inflammation. However, it remained unclear how activating these molecules would lead to airway inflammation. In this study, we examined whether OSCN^- produced via the pendrin/peroxidase/Duox pathway causes inflammation via airway epithelial cells. In an in vitro OSCN^- production system, OSCN^-, but not H₂O₂, activated NF-κB, a transcription factor critical for inflammatory responses, in the airway epithelial cells. OSCN^- was sensed by protein kinase A (PKA) followed by formation of the dimerization of PKA. The dimerized PKA, the active form, was critical in activating NF-κB. Detoxifying H₂O₂, mainly by catalase, enabled the dominant abilities of OSCN^- to dimerize PKA and activate NF-κB, compared with untreated H₂O₂. Furthermore, OSCN^- in high doses caused necrosis of the cells, inducing release of IL-33, a trigger to initiate type 2 inflammation. These results demonstrate that OSCN^- in low doses activates NF-κB via PKA in airway epithelial cells, whereas OSCN^- in high doses causes necrosis, suggesting an important role in airway allergic inflammation for the production of OSCN^- via the pendrin/peroxidase/Duox pathway.