Nfatc4 Deficiency Attenuates Ototoxicity by Suppressing Tnf-Mediated Hair Cell Apoptosis in the Mouse Cochlea

Abstract

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.

Treatment With Calcineurin Inhibitor FK506 Attenuates Noise-Induced Hearing Loss

“…In our study, the expression of NFAT3 in OHC nuclei is significantly increased in a timedependent fashion after exposure to moderate PTS noise, in agreement with the notion that the NFAT transcription factor family can be activated by CaN. OHC death, as a consequence of increased nuclear NFAT3, is compatible with an earlier report that application of an NFAT inhibitor on explants attenuates gentamicin-induced hair cell death (Bodmer et al, 2016) and is in line with the recent report showing that Nfatc3 (NFAT3) deficiency in mice attenuates ototoxicity by suppressing TNFmediated hair cell apoptosis (Zhang et al, 2019). NFAT forms a cooperative complex with AP-1 or other bZIP proteins through its binding site (Macián et al, 2001).…”

“…Recently, a report showed that Nfatc3 (NFAT3) deficiency in mice attenuates ototoxicity by suppressing TNF-mediated hair cell apoptosis (Zhang et al, 2019). In fact, overproduction of both ROS and cytokines has been well documented in noise trauma with loss of OHCs (Yamane et al, 1995;Shi et al, 2003;Yamashita et al, 2005;Fujioka et al, 2006;Le Prell et al, 2007;Dhukhwa et al, 2019;Fetoni et al, 2019;Frye et al, 2019).…”

Noise-Induced Hearing Loss: Updates on Molecular Targets and Potential Interventions

“…It is reported that noise-induced increase of TNF- α can be regulated by nuclear factor of activated T cells 4 (Nfatc4), a well-researched transcription factor served as proinflammatory cytokine inducer. Nfatc4 knockout mice show resistance to TNF- α -mediated hair cell apoptosis triggered by intense noise [ 95 ]. Notably, TNF- α is testified to be able to induce calcium influx through ERK-dependent activation of TRPV1.…”

Radiation-induced neuropathies in head and neck cancer: prevention and treatment modalities

“…These include agents as N-acetylcysteine, sodium thiosulphate, D-methionine, lipoic acid, ebselen, diethyldithiocarbamate, 4-methylthiobenzoic acid, sodium salicylate, neurotrophin-3, BDNF (Brain-derived neurotrophic factor), flunarizine and NOX3 RNA silencing [57,65]. Under basal conditions, Nfatc4 double knockout mice abrogated TNF-mediated apoptosis in auditory hair cells [66]. In a sudden loss of sensorineural hearing loss, intratympanic or oral administration of steroids was effective in auditory recovery [67].…”