EphA2 Recognizes Dermatophagoides Pteronyssinus to Mediate Airway Inflammation in Asthma

Th2-low asthma is mostly steroid-resistant severe asthma, and its specific pathogenesis has not yet been fully elucidated. We found that IL-6 and IL-8 were highly expressed in the sputum supernatant of severe asthma and ephrin type-A receptor 2 (EphA2) was highly expressed on bronchial epithelial cells. So, is there a connection between these two phenomena? To clarify this question, we stimulated bronchial epithelial cells 16HBE with Dermatophagoides pteronyssinus and its compontents LPS, respectively, and detected the activation of EphA2, the activation of downstream pathways, and the secretion of inflammatory cytokines. A mouse asthma model was established, and the therapeutic effect of inhibiting EphA2 on mouse asthma was examined. The results showed that D. pteronyssinus and its component LPS could phosphorylate EphA2 on 16HBE, activate the downstream signaling pathways STAT3 and p38 MAPK, and promote the secretion of IL-6 and IL-8. After knockout of EphA2 on 16HBE, the activation of inflammatory pathways was attenuated, and the secretion of IL-6 and IL-8 was significantly reduced. After inhibiting the expression of EphA2 in the airway of mice, the airway hyperresponsiveness and airway inflammation in mice were significantly reduced, and the expression levels of IL-6, IL-17F, IL-1α, IL-1β and TNF in bronchoalveolar lavage fluid and lung tissue were significantly decreased. Our study uncovers a novel role for EphA2 expressed on airway epithelial cells in the pathogenesis of asthma; EphA2 recognizes D. pteronyssinus or its component LPS to promote the secretion of IL-6 and IL-8 from airway epithelial cell to mediate airway inflammation. Therefore, it is possible to provide a new molecular therapy for severe asthma.