Nfatc4 Deficiency Attenuates Ototoxicity by Suppressing Tnf-Mediated Hair Cell Apoptosis in the Mouse Cochlea
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 st...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.01660/full |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Yanping Zhang Yanping Zhang Diyan Chen Diyan Chen Liping Zhao Liping Zhao Wen Li Wen Li Yusu Ni Yusu Ni Yan Chen Yan Chen Huawei Li Huawei Li Huawei Li |
| spellingShingle |
Yanping Zhang Yanping Zhang Diyan Chen Diyan Chen Liping Zhao Liping Zhao Wen Li Wen Li Yusu Ni Yusu Ni Yan Chen Yan Chen Huawei Li Huawei Li Huawei Li Nfatc4 Deficiency Attenuates Ototoxicity by Suppressing Tnf-Mediated Hair Cell Apoptosis in the Mouse Cochlea Frontiers in Immunology Nfatc4 inflammation inner ear cochlear hair cells cell apoptosis hearing loss |
| author_facet |
Yanping Zhang Yanping Zhang Diyan Chen Diyan Chen Liping Zhao Liping Zhao Wen Li Wen Li Yusu Ni Yusu Ni Yan Chen Yan Chen Huawei Li Huawei Li Huawei Li |
| author_sort |
Yanping Zhang |
| title |
Nfatc4 Deficiency Attenuates Ototoxicity by Suppressing Tnf-Mediated Hair Cell Apoptosis in the Mouse Cochlea |
| title_short |
Nfatc4 Deficiency Attenuates Ototoxicity by Suppressing Tnf-Mediated Hair Cell Apoptosis in the Mouse Cochlea |
| title_full |
Nfatc4 Deficiency Attenuates Ototoxicity by Suppressing Tnf-Mediated Hair Cell Apoptosis in the Mouse Cochlea |
| title_fullStr |
Nfatc4 Deficiency Attenuates Ototoxicity by Suppressing Tnf-Mediated Hair Cell Apoptosis in the Mouse Cochlea |
| title_full_unstemmed |
Nfatc4 Deficiency Attenuates Ototoxicity by Suppressing Tnf-Mediated Hair Cell Apoptosis in the Mouse Cochlea |
| title_sort |
nfatc4 deficiency attenuates ototoxicity by suppressing tnf-mediated hair cell apoptosis in the mouse cochlea |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Immunology |
| issn |
1664-3224 |
| publishDate |
2019-07-01 |
| description |
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. |
| topic |
Nfatc4 inflammation inner ear cochlear hair cells cell apoptosis hearing loss |
| url |
https://www.frontiersin.org/article/10.3389/fimmu.2019.01660/full |
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doaj-0d7819ae092d417db716fbaa522683d82020-11-25T01:10:28ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-07-011010.3389/fimmu.2019.01660450228Nfatc4 Deficiency Attenuates Ototoxicity by Suppressing Tnf-Mediated Hair Cell Apoptosis in the Mouse CochleaYanping Zhang0Yanping Zhang1Diyan Chen2Diyan Chen3Liping Zhao4Liping Zhao5Wen Li6Wen Li7Yusu Ni8Yusu Ni9Yan Chen10Yan Chen11Huawei Li12Huawei Li13Huawei Li14State Key Laboratory of Medical Neurobiology, Department of Affiliated Eye and ENT Hospital, ENT Institute and Otorhinolaryngology, Institutes of Biomedical Sciences and the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, ChinaNHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, ChinaState Key Laboratory of Medical Neurobiology, Department of Affiliated Eye and ENT Hospital, ENT Institute and Otorhinolaryngology, Institutes of Biomedical Sciences and the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, ChinaNHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, ChinaState Key Laboratory of Medical Neurobiology, Department of Affiliated Eye and ENT Hospital, ENT Institute and Otorhinolaryngology, Institutes of Biomedical Sciences and the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, ChinaNHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, ChinaState Key Laboratory of Medical Neurobiology, Department of Affiliated Eye and ENT Hospital, ENT Institute and Otorhinolaryngology, Institutes of Biomedical Sciences and the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, ChinaNHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, ChinaState Key Laboratory of Medical Neurobiology, Department of Affiliated Eye and ENT Hospital, ENT Institute and Otorhinolaryngology, Institutes of Biomedical Sciences and the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, ChinaNHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, ChinaState Key Laboratory of Medical Neurobiology, Department of Affiliated Eye and ENT Hospital, ENT Institute and Otorhinolaryngology, Institutes of Biomedical Sciences and the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, ChinaNHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, ChinaState Key Laboratory of Medical Neurobiology, Department of Affiliated Eye and ENT Hospital, ENT Institute and Otorhinolaryngology, Institutes of Biomedical Sciences and the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, ChinaNHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, ChinaShanghai Engineering Research Centre of Cochlear Implant, Shanghai, ChinaThe 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.https://www.frontiersin.org/article/10.3389/fimmu.2019.01660/fullNfatc4inflammationinner earcochlear hair cellscell apoptosishearing loss |