Liu Jinlan, Chen Huiying, Lin Xiaoyu, Zhu Xiaoting, Huang Jialin, Xu Wenfeng, Tan Ming, Su Jiping
Department of Otolaryngology-Head & Neck Surgery, First Afliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; Department of Otolaryngology-Head & Neck Surgery, Guangxi International Zhuang Medicine Hospital, Nanning, Guangxi, China.
Department of Otolaryngology-Head & Neck Surgery, First Afliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
Neuroscience. 2023 May 1;517:84-95. doi: 10.1016/j.neuroscience.2023.01.015. Epub 2023 Jan 23.
Melatonin supplementation has been shown to delay age-related hearing loss (ARHL) progression. Previously, melatonin was found to inhibit neuronal mitochondrial DNA (mtDNA) release, as well as inhibit cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling, thereby delaying the onset of central nervous system diseases. Therefore, we hypothesized that melatonin may delay the progression of hearing loss in the C57BL/6J presbycusis mouse model by inhibiting cGAS-STING signaling in the auditory pathway. Oral melatonin at 10 mg/kg/d was administered to 3-month-old C57BL/6J mice until 12 months of age. The auditory brainstem response (ABR) threshold was used to assess their hearing ability. By real-time polymerase chain reaction and Western blot analysis, the levels of cytosolic mtDNA, cGAS/STING, and cytokines were examined in the mouse cochlea, inferior colliculus, and auditory cortex. We found that the 12-month-old control mice exhibited significant hearing loss, increased cytosolic mtDNA, increased expression of inflammatory factors TNF-α, IL-6, IFN-β, Cxcl10, and Ifit3, up-regulated cGAS and STING expression, and enhanced interferon regulatory factor 3 (IRF3) phosphorylation in the C57BL/6J mouse cochlea, inferior colliculus, and auditory cortex. Melatonin treatment significantly improved hearing, decreased cytosolic mtDNA, suppressed the expression of inflammatory cytokines TNF-α, IL-6, IFN-β, Ifit3, and Cxcl10, down-regulated cGAS and STING expression, and attenuated IRF3 phosphorylation in the C57BL/6J mouse cochlea, inferior colliculus, and auditory cortex. This study suggested that melatonin had a protective effect on auditory function in the C57BL/6J presbycusis mouse model, which may be mediated through reducing mtDNA release, inhibiting the cGAS-STING signaling pathway in the auditory pathway.
补充褪黑素已被证明可延缓年龄相关性听力损失（ARHL）的进展。此前，人们发现褪黑素可抑制神经元线粒体DNA（mtDNA）释放，并抑制环磷酸鸟苷-腺苷酸合成酶（cGAS）-干扰素基因刺激因子（STING）信号传导，从而延缓中枢神经系统疾病的发病。因此，我们推测褪黑素可能通过抑制听觉通路中的cGAS-STING信号传导来延缓C57BL/6J老年性聋小鼠模型的听力损失进展。对3月龄的C57BL/6J小鼠每日口服10 mg/kg的褪黑素，直至12月龄。用听觉脑干反应（ABR）阈值评估它们的听力能力。通过实时聚合酶链反应和蛋白质免疫印迹分析，检测小鼠耳蜗、下丘和听觉皮层中胞质mtDNA、cGAS/STING和细胞因子的水平。我们发现，12月龄的对照小鼠表现出明显的听力损失、胞质mtDNA增加、炎症因子TNF-α、IL-6、IFN-β、Cxcl10和Ifit3的表达增加、cGAS和STING表达上调，以及C57BL/6J小鼠耳蜗、下丘和听觉皮层中干扰素调节因子3（IRF3）磷酸化增强。褪黑素治疗显著改善了听力，降低了胞质mtDNA，抑制了炎症细胞因子TNF-α、IL-6、IFN-β、Ifit3和Cxcl10的表达，下调了cGAS和STING表达，并减弱了C57BL/6J小鼠耳蜗、下丘和听觉皮层中IRF3的磷酸化。本研究表明，褪黑素对C57BL/6J老年性聋小鼠模型的听觉功能具有保护作用，这可能是通过减少mtDNA释放、抑制听觉通路中的cGAS-STING信号通路来介导的。
