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OMVs of Pseudomonas aeruginosa extracted from chronic suppurative otitis media trigger ototoxicity: possible relation to activation of NLRP3 inflammasome
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DOI：10.1186/s12974-026-03990-1.png)
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Abstract
En 中文
Chronic suppurative otitis media (CSOM) can lead to sensorineural hearing loss (SNHL), but the underlying mechanisms remain incompletely understood. This study aimed to investigate whether the outer membrane vesicles (OMVs) from Pseudomonas aeruginosa (P.aeruginosa), a common CSOM pathogen, can induce ototoxicity via activation of NLRP3 inflammasome. A CSOM model was established in C57BL/6 mice by intratympanic injection of P.aeruginosa-derived OMVs. The pathological changes in the middle and inner ear and the activation of the NLRP3 inflammasome pathway were evaluated using cochlear tissues from model mice, together with in vitro models employing organ of Corti-derived (HEI-OC1) cells and postnatal day 4 (P4) mouse cochlear explants, through histopathological staining, immunoassays, and RNA sequencing. The protective role of the NLRP3 inhibitor MCC950 was additionally investigated. P. aeruginosa OMVs induced dose- and time-dependent reductions in cellular metabolic activity in the HEI-OC1 organ of Corti cell line, as well as cochlear hair cell damage and NLRP3 inflammasome activation in postnatal P4 cochlear explants. In vivo, OMV inoculation provoked CSOM and inner ear injury within 14 days, accompanied by significant hair cell loss. RNA-sequencing analysis of CSOM mouse cochleae identified 2583 differentially expressed genes, predominantly enriched in inflammatory pathways, with marked upregulation of NLRP3, Pycard, Casp1, GSDMD, and IL-1β. Treatment with MCC950 significantly alleviated inner ear inflammation, preserved cochlear morphology, reduced hair cell damage, and suppressed the expression of NLRP3, ASC, caspase-1, and GSDMD. These findings provide evidence supporting the hypothesis that P. aeruginosa OMVs contribute to CSOM-associated cochlear damage both in vivo and in vitro, a process associated with NLRP3 inflammasome activation within the inner ear. While causality cannot be fully established, inhibition of NLRP3 signaling with MCC950 mitigated inner ear injury and suppressed pyroptosis-related effectors, implying its potential as a novel therapeutic strategy for CSOM-related SNHL.
Keywords:
Outer membrane vesicles
Chronic suppurative otitis media
Sensorineural hearing loss
Pseudomonas aeruginosa OMVs
NLRP3 inflammasome activation
Pyroptosis in cochlear hair cells
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