METTL3-mediated N6-methyladenosine modification regulates NLRP3 inflammasome activation in chronic suppurative otitis media

IF 2.5 2区医学 Q1 AUDIOLOGY & SPEECH-LANGUAGE PATHOLOGY

Hearing Research Pub Date : 2025-10-04 DOI:10.1016/j.heares.2025.109439

Yuanyuan Yang , Jianxin Qiu

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Abstract

Background

Chronic suppurative otitis media (CSOM) is a common inflammatory condition characterized by persistent ear discharge and hearing loss. Recent studies have highlighted the importance of the NLRP3 inflammasome in the pathogenesis of various inflammatory diseases, including CSOM. Here, we investigated the role of METTL3 and N⁶-methyladenosine (m⁶A) modification in the regulation of NLRP3 inflammasome activation in CSOM.

Methods

CSOM model mice were established by intraperitoneally injected with lipopolysaccharide (LPS) and middle ear tissues were collected for analysis. Inflammatory cytokines including TNF-α, IL-1β, IFN-γ, and IL-6 were evaluated, as well as the levels of m⁶A related genes. The potential regulatory effects of METTL3 mediated m⁶A modification of NLRP3 was further studied to explain the inflammatory response in CSOM.

Results

We found that METTL3 overexpression increased the m⁶A level and mRNA stability of NLRP3, leading to enhanced inflammasome activation and production of inflammatory cytokines. Conversely, silencing METTL3 reduced NLRP3 expression and inflammasome activity. Rescue experiments with NLRP3 overexpression confirmed that the effects of METTL3 on inflammation were mediated through NLRP3. Additionally, the NLRP3 inhibitor MCC950 reversed the pro-inflammatory effects of METTL3 overexpression.

Conclusions

Our findings suggest that METTL3-mediated m⁶A modification plays a critical role in NLRP3 inflammasome activation and the inflammatory response in CSOM. Targeting the METTL3/NLRP3 axis may provide a novel therapeutic strategy for the treatment of CSOM.

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mettl3介导的n6 -甲基腺苷修饰调节慢性化脓性中耳炎NLRP3炎性体的激活

慢性化脓性中耳炎（CSOM）是一种常见的炎症性疾病，其特征是持续的耳部分泌物和听力丧失。最近的研究强调了NLRP3炎性小体在包括CSOM在内的各种炎症性疾病发病机制中的重要性。在这里，我们研究了METTL3和n6 -甲基腺苷（m6A）修饰在CSOM中调节NLRP3炎性体激活中的作用。方法通过腹腔注射脂多糖（LPS）建立小鼠scsom模型，收集小鼠中耳组织进行分析。评估炎症因子包括TNF-α、IL-1β、IFN-γ和IL-6，以及m6A相关基因的水平。我们进一步研究了METTL3介导的m6A修饰NLRP3的潜在调节作用，以解释CSOM中的炎症反应。结果METTL3过表达增加了NLRP3的m6A水平和mRNA稳定性，导致炎症小体活化和炎症细胞因子的产生增强。相反，沉默METTL3会降低NLRP3的表达和炎症小体的活性。NLRP3过表达的抢救实验证实了METTL3对炎症的作用是通过NLRP3介导的。此外，NLRP3抑制剂MCC950逆转了METTL3过表达的促炎作用。结论mettl3介导的m6A修饰在CSOM NLRP3炎症小体激活和炎症反应中起关键作用。靶向METTL3/NLRP3轴可能为CSOM的治疗提供一种新的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Hearing Research 医学-耳鼻喉科学

CiteScore

5.30

自引率

14.30%

发文量

163

审稿时长

75 days

期刊介绍： The aim of the journal is to provide a forum for papers concerned with basic peripheral and central auditory mechanisms. Emphasis is on experimental and clinical studies, but theoretical and methodological papers will also be considered. The journal publishes original research papers, review and mini- review articles, rapid communications, method/protocol and perspective articles. Papers submitted should deal with auditory anatomy, physiology, psychophysics, imaging, modeling and behavioural studies in animals and humans, as well as hearing aids and cochlear implants. Papers dealing with the vestibular system are also considered for publication. Papers on comparative aspects of hearing and on effects of drugs and environmental contaminants on hearing function will also be considered. Clinical papers will be accepted when they contribute to the understanding of normal and pathological hearing functions.