Nfatc4 Deficiency Attenuates Ototoxicity by Suppressing Tnf-Mediated Hair Cell Apoptosis in the Mouse Cochlea
Nfatc4 Deficiency Attenuates Ototoxicity by Suppressing Tnf-Mediated Hair Cell Apoptosis in the Mouse Cochlea
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Nfatc4 缺乏通过抑制 Tnf 介导的小鼠耳蜗毛细胞凋亡来减轻耳毒性
DOI：
10.3389/fimmu.2019.01660
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发表时间：
2019
影响因子：
7.3
通讯作者：
Li Huawei
中科院分区：
文献类型：
--
作者：
Zhang Yanping;Chen Diyan;Zhao Liping;Li Wen;Ni Yusu;Chen Yan;Li Huawei
耳蜗中感觉毛细胞的损失是感音神经性听力损失的主要原因，并且响应于耳蜗损伤的炎症过程和免疫因素已被证明可诱导毛细胞凋亡。Nfatc 4在耳蜗中的表达和功能仍不清楚。在这项研究中，我们研究了Nfatc 4在小鼠耳蜗中的表达，并使用Nfatc 4 −/−小鼠探索其功能。我们首次发现Nfatc 4在耳蜗毛细胞中表达。在Nfatc 4 −/−小鼠中，耳蜗毛细胞发育和听力功能正常，这表明Nfatc 4对耳蜗发育并不重要。然后，我们发现，当毛细胞受到耳毒性药物的攻击时，Nfatc 4被激活并从细胞质易位到细胞核，这伴随着TNF及其下游靶标的表达增加和随后的毛细胞凋亡。最后，我们证明了Nfatc 4缺陷型毛细胞对耳毒性药物和噪声暴露引起的损伤的敏感性低于野生型对照。TNF介导的凋亡途径在Nfatc 4缺陷耳蜗上皮中减弱，这可能是Nfatc 4缺陷毛细胞对损伤敏感性降低的原因。这些结果表明，通过抑制Nfatc 4活化来改善炎症介导的毛细胞凋亡可能对预防耳毒性药物或噪声暴露引起的感音神经性听力损失具有重要的治疗价值。
The loss of sensory hair cells in the cochlea is the major cause of sensorineural hearing loss, and inflammatory processes and immune factors in response to cochlear damage have been shown to induce hair cell apoptosis. The expression and function of Nfatc4 in the cochlea remains unclear. In this study, we investigated the expression of Nfatc4 in the mouse cochlea and explored its function using Nfatc4−/− mice. We first showed that Nfatc4 was expressed in the cochlear hair cells. Cochlear hair cell development and hearing function were normal in Nfatc4−/− mice, suggesting that Nfatc4 is not critical for cochlear development. We then showed that when the hair cells were challenged by ototoxic drugs Nfatc4 was activated and translocated from the cytoplasm to the nucleus, and this was accompanied by increased expression of Tnf and its downstream targets and subsequent hair cell apoptosis. Finally, we demonstrated that Nfatc4-deficient hair cells showed lower sensitivity to damage induced by ototoxic drugs and noise exposure compared to wild type controls. The Tnf-mediated apoptosis pathway was attenuated in Nfatc4-deficient cochlear epithelium, and this might be the reason for the reduced sensitivity of Nfatc4-deficient hair cells to injury. These findings suggest that the amelioration of inflammation-mediated hair cell apoptosis by inhibition of Nfatc4 activation might have significant therapeutic value in preventing ototoxic drug or noise exposure-induced sensorineural hearing loss.