Inhibition of the NLRP3 inflammasome attenuates spiral ganglion neuron degeneration in aminoglycoside-induced hearing loss

Jia Fang; Zhuangzhuang Li; Pengjun Wang; Xiaoxu Zhang; Song Mao; Yini Li; Dongzhen Yu; Xiaoyan Li; Yazhi Xing; Haibo Shi; Shankai Yin

doi:10.4103/NRR.NRR-D-23-01879

Inhibition of the NLRP3 inflammasome attenuates spiral ganglion neuron degeneration in aminoglycoside-induced hearing loss

Neural Regen Res. 2025 Oct 1;20(10):3025-3039. doi: 10.4103/NRR.NRR-D-23-01879. Epub 2024 Jun 3.

Authors

Jia Fang^{1

2}, Zhuangzhuang Li¹, Pengjun Wang¹, Xiaoxu Zhang¹, Song Mao¹, Yini Li¹, Dongzhen Yu¹, Xiaoyan Li², Yazhi Xing¹, Haibo Shi¹, Shankai Yin¹

Affiliations

¹ Department of Otolaryngology Head and Neck Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine; Otolaryngology Institute of Shanghai Jiao Tong University; Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, China.
² Department of Otorhinolaryngology-Head and Neck Surgery, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

PMID: 39610108
DOI: 10.4103/NRR.NRR-D-23-01879

Abstract

JOURNAL/nrgr/04.03/01300535-202510000-00031/figure1/v/2024-11-26T163120Z/r/image-tiff Aminoglycosides are a widely used class of antibacterials renowned for their effectiveness and broad antimicrobial spectrum. However, their use leads to irreversible hearing damage by causing apoptosis of hair cells as their direct target. In addition, the hearing damage caused by aminoglycosides involves damage of spiral ganglion neurons upon exposure. To investigate the mechanisms underlying spiral ganglion neuron degeneration induced by aminoglycosides, we used a C57BL/6J mouse model treated with kanamycin. We found that the mice exhibited auditory deficits following the acute loss of outer hair cells. Spiral ganglion neurons displayed hallmarks of pyroptosis and exhibited progressive degeneration over time. Transcriptomic profiling of these neurons showed significant upregulation of genes associated with inflammation and immune response, particularly those related to the NLRP3 inflammasome. Activation of the canonical pyroptotic pathway in spiral ganglion neurons was observed, accompanied by infiltration of macrophages and the release of proinflammatory cytokines. Pharmacological intervention targeting NLRP3 using Mcc950 and genetic intervention using NLRP3 knockout ameliorated spiral ganglion neuron degeneration in the injury model. These findings suggest that NLRP3 inflammasome-mediated pyroptosis plays a role in aminoglycoside-induced spiral ganglion neuron degeneration. Inhibition of this pathway may offer a potential therapeutic strategy for treating sensorineural hearing loss by reducing spiral ganglion neuron degeneration.