RAGE Inhibition Reduces Allergen-Induced ATP Release, Ca²⁺Mobilization and Type 2 Immunity In Airways

Allergens from the fungus Alternaria alternata promote secretion of alarmins from the airway epithelium including ATP, IL-33 and both genomic and mitochondrial DNA fragments, which produce type 2 immune responses in airways. Alternaria -induced oxidative stress activates ATP release by opening apical voltage-dependent anion channels (VDAC-1) and stimulating exocytosis of ATP. This investigation demonstrated that treatment of human bronchial epithelial (hBE) cells with a selective peptide antagonist or small molecule inhibitor (FPS-ZM 1 ) of the receptor for advanced glycation end products (RAGE), reduced Alternaria -evoked ATP secretion, decreasing the initial rate by ~40%. Furthermore, the Alternaria -induced increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) was inhibited by ~75% following pretreatment with RAGE antagonist peptide. Intranasal administration of Alternaria extract (50 μg) produced a significant increase in IL-33 secretion into bronchoalveolar lavage (BAL) fluid, which was inhibited in RAGE-deficient ( Ager -/- ) mice. Moreover, Alternaria -induced increases in IL-5 and IL-13 secretion into BAL fluid were also significantly reduced in Ager -/- mice. These findings support the conclusion that Alternaria -dependent ATP release and Ca 2+ mobilization was dependent in part on RAGE activation and that RAGE antagonists have the potential of reducing type 2 immune responses in airways following Alternaria allergen exposure. This study was supported by grants from the NIH (R01A1128729 & 1R01AI169530) to HK and SMO and by the Minnesota Agricultural Experiment station grant (AES0016134) to SMO. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.