Role of IL‐18‐transformed CD274‐expressing eosinophils in promoting airway obstruction in experimental asthma

Abstract Background IL‐5‐dependent residential and IL‐18‐transformed pathogenic eosinophils have been reported; however, the role of IL‐18‐transformed CD274‐expressing pathogenic eosinophils compared to IL‐5‐generated eosinophils in promoting airway obstruction in asthma has not yet been examined. Methods Eosinophils are detected by tissue anti‐MBP and anti‐EPX immunostaining, CD274 expression by flow cytometry, and airway resistance using the Buxco FinePointe RC system. Results We show that A . fumigatus ‐challenged wild‐type mice, and different gene‐deficient mice including naïve CC10‐IL‐18‐transgenic mice, accumulate mostly peribronchial and perivascular CD274‐expressing eosinophils except naïve CD2‐IL‐5‐transgenic mice. Additionally, we show that CD2‐IL‐5 transgenic mice following rIL‐18 treatment accumulate high number of CD274‐expressing perivascular and peribronchial eosinophils with induced collagen, goblet cell hyperplasia and airway resistance compared to saline‐challenged CD2‐IL5 transgenic mice. Furthermore, we also show that even A . fumigatus ‐challenged IL ‐ 5 −/− mice and rIL‐18 given ΔdblGATA mice accumulate CD274‐expressing eosinophil‐associated asthma pathogenesis including airway obstruction. Most importantly, we provide evidence that neutralization of CD274 and IL‐18 in A . fumigatus ‐challenged mice ameliorate experimental asthma. Taken together, the data presented are clinically significant in establishing that anti‐IL‐18 neutralization is a novel immunotherapy to restrict asthma pathogenesis. Conclusions We demonstrate that IL‐18 is critical for inducing asthma pathogenesis, and neutralization of CD274 is a potential immunotherapeutic strategy for asthma.