Inhibition of the Activation and Recruitment of Microglia-Like Cells Protects Against Neomycin-Induced Ototoxicity
Inhibition of the Activation and Recruitment of Microglia-Like Cells Protects Against Neomycin-Induced Ototoxicity
复制标题
抑制小胶质细胞样细胞的激活和募集可防止新霉素引起的耳毒性
DOI：
10.1007/s12035-014-8712-y
复制
发表时间：
2015-02-01
影响因子：
5.1
通讯作者：
Li, Huawei
中科院分区：
文献类型：
--
作者：
Sun, Shan;Yu, Huiqian;Li, Huawei
新霉素等氨基糖苷类 (AG) 抗生素最不幸的副作用之一是它们针对感觉毛细胞 (HC)，并可能导致永久性听力损伤。我们观察到施用新霉素后内耳（耳蜗）中 HC 损失和小胶质细胞样细胞 (MLC) 激活。我们重点关注 CX3CL1（一种在神经元和内皮细胞上表达的膜结合糖蛋白），以此来了解 MLC 如何被激活以及这些细胞在 HC 损失中所起的作用。 CX3CL1 是 CX3CR1 的唯一配体，CX3CR1 是表达于巨噬细胞和 MLC 表面的趋化因子受体。体外实验表明，新霉素处理后耳蜗中CX3CL1和CX3CR1的表达水平增加，并且CX3CL1在HCs上表达，而CX3CR1在MLCs上表达。当用1μg/mL外源CX3CL1培养时，MLC被CX3CL1激活，耳蜗中细胞因子水平增加，导致HC细胞凋亡。在 CX3CR1 敲除小鼠中，当耳蜗外植体与新霉素一起体外培养时，存活的耳蜗 HC 数量明显多于野生型小鼠。此外，用米诺环素抑制 MLC 的激活可减少新霉素诱导的 HC 损失，并改善新霉素治疗小鼠体内的听力功能。我们的结果表明，CX3CL1 诱导的 MLC 激活在诱导 HC 死亡中发挥重要作用，并为 CX3CL1 和 CX3CR1 作为预防听力损失的有希望的新治疗靶点提供了证据。
One of the most unfortunate side effects of aminoglycoside (AG) antibiotics such as neomycin is that they target sensory hair cells (HCs) and can cause permanent hearing impairment. We have observed HC loss and microglia-like cell (MLC) activation in the inner ear (cochlea) following neomycin administration. We focused on CX3CL1, a membrane-bound glycoprotein expressed on neurons and endothelial cells, as a way to understand how the MLCs are activated and the role these cells play in HC loss. CX3CL1 is the exclusive ligand for CX3CR1, which is a chemokine receptor expressed on the surface of macrophages and MLCs. In vitro experiments showed that the expression levels of CX3CL1 and CX3CR1 increased in the cochlea upon neomycin treatment, and CX3CL1 was expressed on HCs, while CX3CR1 was expressed on MLCs. When cultured with 1 mu g/mL exogenous CX3CL1, MLCs were activated by CX3CL1, and the cytokine level was increased in the cochleae leading to apoptosis in the HCs. In CX3CR1 knockout mice, a significantly greater number of cochlear HCs survived than in wild-type mice when the cochlear explants were cultured with neomycin in vitro. Furthermore, inhibiting the activation of MLCs with minocycline reduced the neomycin-induced HC loss and improved the hearing function in neomycin-treated mice in vivo. Our results demonstrate that CX3CL1-induced MLC activation plays an important role in the induction of HC death and provide evidence for CX3CL1 and CX3CR1 as promising new therapeutic targets for the prevention of hearing loss.