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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.
Highlights
Hearing loss is one of the most common sensory disorders in humans, and around 466 million people worldwide have disabling hearing loss
We found that Nuclear factor of activated T cells 4 (Nfatc4) is expressed in the cochlear hair cells and that when the hair cells were challenged by neomycin Nfatc4 translocated to the nucleus, enhanced the expression of tumor necrosis factor (Tnf) and its downstream targets, and led to hair cell apoptosis
Double immunofluorescence staining of Nfatc4 and Sox2 showed that Nfatc4 was not expressed in cochlear supporting cells (Figure 1A)
Summary
Hearing loss is one of the most common sensory disorders in humans, and around 466 million people worldwide have disabling hearing loss. Sensory hair cells in the cochlea detect sound and are responsible for converting mechanical signals into electrical signals, and aminoglycosides and excessive noise exposure can induce caspase-mediated apoptosis in hair cells and lead to hearing loss [1, 2]. The expression levels of pro-inflammatory cytokines, chemokines, Nfatc Deficiency Protects Hair Cells and cell adhesion molecules are increased in both acute and chronic noise-exposed mouse cochleae [3], and several clinical studies have shown that inflammation is a significant component of the mechanisms underlying presbycusis [4]. Tnf expression is increased in the mouse cochlea following acute and chronic noise exposure [3, 5], and exposure to Tnf can induce hair cell damage and apoptosis in cultured cochlear explants [6]
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