Role of IL-18 transformed CD274-expressing eosinophils in promoting airway obstruction in experimental asthma
Allergy. 2021 Nov 20. doi: 10.1111/all.15180. Online ahead of print.
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, different gene-deficient mice including naïve CC10-IL-18-transgenic mice accumulates mostly peribrochial and perivascular CD274-expressing eosinophils except naïve CD2-IL-5-transfgenic mice. Additionally, we show that CD2-IL-5 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 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.