Xu, T.; Zhang, J.; Zhao, H.; Nong, H.; Yang, Q.; Yuan, Y.; Zhao, J.; Zhang, X.; Li, Y.; Tun, Z. M. M.; Bekale, L.; Cao, Z.

Chronic suppurative otitis media (CSOM) is not just a bacterial infection of the middle ear but a leading cause of sensorineural hearing loss (SNHL). Yet, the mechanisms by which this disease leads to SNHL have remained elusive until now. Our study uncovers how Pseudomonas aeruginosa outer membrane vesicles (OMVs) directly damage cochlear hair cells. In both in vitro and in vivo models, OMVs were found to attack outer hair cells (OHCs) in the basal cochlea, which are responsible for high-frequency hearing and independent of macrophage activity. Beyond this damage, OMVs trigger intense inflammation, marked by increased pro-inflammatory M1 macrophages, which worsens the damage. OMVs also activate the NLRP3 inflammasome, driving inflammatory cell death through pyroptosis. RNA sequencing and proteomics confirmed this pathway, and treatment with the NLRP3 inhibitor MCC950 significantly reduced hearing loss in animal models. These findings reveal a new therapeutic target in the NLRP3 inflammasome, offering hope for innovative treatments to prevent hearing loss in CSOM patients.