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顺铂诱导耳蜗边缘细胞焦亡及其机制研究。

Cochlear Marginal Cell Pyroptosis Is Induced by Cisplatin NLRP3 Inflammasome Activation.

机构信息

Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

出版信息

Front Immunol. 2022 Apr 20;13:823439. doi: 10.3389/fimmu.2022.823439. eCollection 2022.

DOI:10.3389/fimmu.2022.823439
PMID:35529876
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9067579/
Abstract

Better understanding the mechanism of cisplatin-induced ototoxicity is of great significance for clinical prevention and treatment of cisplatin-related hearing loss. However, the mechanism of cisplatin-induced inflammatory response in cochlear stria vascularis and the mechanism of marginal cell (MC) damage have not been fully clarified. In this study, a stable model of cisplatin-induced MC damage was established , and the results of PCR and Western blotting showed increased expressions of NLRP3, Caspase-1, IL-1β, and GSDMD in MCs. Incomplete cell membranes including many small pores appearing on the membrane were also observed under transmission electron microscopy and scanning electron microscopy. In addition, downregulation of NLRP3 by small interfering RNA can alleviate cisplatin-induced MC pyroptosis, and reducing the expression level of TXNIP possesses the inhibition effect on NLRP3 inflammasome activation and its mediated pyroptosis. Taken together, our results suggest that NLRP3 inflammasome activation may mediate cisplatin-induced MC pyroptosis in cochlear stria vascularis, and TXNIP is a possible upstream regulator, which may be a promising therapeutic target for alleviating cisplatin-induced hearing loss.

摘要

更好地了解顺铂诱导的耳毒性的机制对于临床预防和治疗顺铂相关性听力损失具有重要意义。然而，顺铂诱导耳蜗血管纹中的炎症反应的机制以及边缘细胞（MC）损伤的机制尚未完全阐明。在本研究中，建立了稳定的顺铂诱导 MC 损伤模型，PCR 和 Western blot 结果显示 MC 中 NLRP3、Caspase-1、IL-1β和 GSDMD 的表达增加。透射电子显微镜和扫描电子显微镜下还观察到不完全的细胞膜，包括膜上出现的许多小孔。此外，小干扰 RNA 下调 NLRP3 可以减轻顺铂诱导的 MC 细胞焦亡，并且降低 TXNIP 的表达水平对 NLRP3 炎性小体的激活及其介导的细胞焦亡具有抑制作用。综上所述，我们的结果表明 NLRP3 炎性小体的激活可能介导顺铂诱导的耳蜗血管纹中的 MC 细胞焦亡，而 TXNIP 可能是一个潜在的上游调节剂，这可能是缓解顺铂诱导的听力损失的有希望的治疗靶点。

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