Perturbation of EPHA2 and EFNA1 trans binding amplifies inflammatory response in airway epithelial cells

The interactions between EPH receptors and ephrin (EFN) ligands play a crucial role in maintaining epithelial integrity and aiding in defense against infections. However, it remains unclear how the EPH-EFN <i>trans</i>-binding changes during infections and how this alteration affects inflammatory response. Here we report that pathogen-associated molecular patterns (PAMPs) disrupt the EPHA2-EFNA1 <i>trans</i>-binding in airway epithelial cells (AECs). Mechanistically, flagellin induces the TLR5-dependent EFNA1 cleavage through the metalloproteinase ADAM9 concomitant with the activation of ligand-independent EPHA2 signaling. We found that the ablation of EPHA2 reduced the responsiveness of respiratory inflammation induced by flagellin and <i>Pseudomonas aeruginosa</i> both <i>in vitro</i> and <i>in vivo</i>. Notably, even in the absence of PAMPs, the inflammatory response in AECs was stimulated by forcibly induced EFNA1 shedding. These findings illustrate that the perturbation of the EPHA2-EFNA1 <i>trans</i>-binding acts as a sensing mechanism for infections and amplifies the inflammatory response, providing a defense mechanism for respiratory epithelia.