Abstract
Various stressors, such as loud sounds and the effects of aging, impair the function and viability of the cochlear sensory cells, the hair cells. Stressors trigger pathophysiological changes in the cochlear non-sensory cells as well. We have here studied the stress response mounted in the lateral wall of the cochlea during acute noise stress and during age-related chronic stress. We have used the activation of JNK/c-Jun, ERK, and NF-κB pathways as a readout of the stress response, and the expression of the FoxO3 transcription factor as a possible additional player in cellular stress. In the aging cochlea, NF-κB transcriptional activity was strongly induced in the stria vascularis of the lateral wall. This induction was linked with the atrophy of the stria vascularis, suggesting a role for NF-κB signaling in mediating age-related strial degeneration. Acutely following noise exposure, the JNK/c-Jun, ERK, and NF-κB pathways were activated in the spiral ligament of the lateral wall of CBA/Ca mice. This activation was concomitant with the morphological transformation of macrophages, suggesting that the upregulation of stress signaling leads to macrophage activation. In contrast, C57BL/6J mice lacked these responses. Only the combination of noise exposure and a systemic stressor, lipopolysaccharide, exceeded the threshold for the activation of stress signaling in the lateral wall of C57BL/6J mice. In addition, we found that, at the young adult age, outer hair cells of CBA/Ca mice are much more vulnerable to loud sounds compared to these cells of C57BL/6J mice. These results suggest that the differential stress response in the lateral wall of the two mouse strains underlies, in part, the differential noise vulnerability of their outer hair cells. Together, we propose that the molecular stress response in the lateral wall modulates the outcome of the stressed cochlea.
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Acknowledgements
We are grateful to Drs P. Barker and M. Mikkola for sharing the NF-κB/LacZ reporter mice with us, and Sanna Sihvo for excellent technical assistance.
Funding
This work was financially supported by Jenny and Antti Wihuri Foundation, Doctoral Programme Brain & Mind University of Helsinki, Instrumentarium Science Foundation, Päivikki and Sakari Sohlberg Foundation, Maud Kuistila Foundation, Kuuloliitto ry, and Finnish Association of Otorhinolaryngology and Head and Neck Surgery.
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The animal experiments were conducted following relevant guidelines for animal work and approved by the National Animal Experiment Board.
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Herranen, A., Ikäheimo, K., Virkkala, J. et al. The Stress Response in the Non-sensory Cells of the Cochlea Under Pathological Conditions—Possible Role in Mediating Noise Vulnerability. JARO 19, 637–652 (2018). https://doi.org/10.1007/s10162-018-00691-2
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DOI: https://doi.org/10.1007/s10162-018-00691-2