Aberrant immune states of the inner ear resultant of aging and lower level noise
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Cochlear immunity is an important process for cochlear homeostasis and diseases. Over the past twenty years, numerous researchers have investigated cochlear immunity as it pertains to inner ear stresses. However, the vast majority of these studies have focused on acute immune activation such as in the event of traumatic noise overexposure, cochlear implantation, pathogenic infection, and ototoxicity. Yet, persistent lower-grade stresses such as aging and lower-level noise exposure are more prevalent in real-world circumstances and certainly affect a greater proportion of the population. Therefore, studies aimed at elucidating the mechanisms and processes of cochlear immune activity subsequent to low-grade stresses is both justified and salient. The studies outlined here sought to reveal the cochlear immune response to age-related sensory cell degeneration, lower level noise exposure, and other chronic cochlear stresses. Specifically, we sought to examine changes in cochlear immune homeostasis following low-grade stresses with and without sensory cell pathogenesis. We first investigated changes in cochlear immunity in the event of age-related degeneration in the inner ear. In the sensory epithelium, macrophages have been identified on the scala tympani side of the basilar membrane. These basilar membrane macrophages are the spatially closest immune cells to sensory cells and are able to respond to and influence sensory cell pathogenesis. While basilar membrane macrophages have been studied in acute cochlear stresses, their behavior in response to chronic sensory cell degeneration is largely unknown. Here we report a systematic observation of the variance in phenotypes, the changes in morphology and distribution of basilar membrane tissue macrophages in different age groups of C57BL/6BL/6J mice, a mouse model of age-related sensory cell degeneration. This study reveals that mature, fully differentiated tissue macrophages, not recently infiltrated monocytes, are the major macrophage population for immune responses to chronic sensory cell death. These macrophages display dynamic changes in their numbers and morphologies as age increases, and the changes are related to the phases of sensory cell degeneration. Notably, macrophage activation precedes sensory cell pathogenesis. Once activated, the activity is maintained until sensory cell degradation is complete. Collectively, these findings suggest that mature tissue macrophages on the basilar membrane are a dynamic group of cells that are capable of vigorous adaptation to changes in the local sensory epithelium environment influenced by sensory cell status.We then investigated the changes to cochlear immune status following lower-level noise stress. Noise exposure producing temporary threshold shifts (TTS) has been demonstrated to cause permanent changes to cochlear physiology and hearing function. Several explanations have been purported to underlie these long-term changes in cochlear function, such as damage to sensory cell stereocilia and synaptic connections between sensory cells and their innervation by spiral ganglion neurons, and demyelination of the auditory nerve. Though these structural defects have been implicated in hearing difficulty, cochlear responses to these degenerative processes remains poorly understood. Here, we report the activation of the cochlear immune system following exposure to lower level noise (LLN) that causes only TTS. Using multiple morphological, molecular and functional parameters, we assessed the responses of macrophages, the primary immune cell population in the cochlea, to the LLN exposure. This study reveals that a LLN that causes only TTS increases the macrophage population in cochlear regions immediately adjacent to sensory cells and their innervations. Many of these cells acquire an activated morphology and express immune molecules, CCL2 and ICAM1 that are important for macrophage adhesion and inflammatory activity. However, LLN exposure reduces macrophage phagocytic ability. While the activated morphology of cochlear macrophages reverses, the complete recovery is not achieved 2 months after the LLN exposure. Taken together, these observations clearly implicate the cochlear immune system in the cochlear response to LLN that causes no permanent threshold change. Collectively, these findings demonstrate that the activation of the immune response in the cochlea, following exposure to lower-intensity noise or subsequent to age-related hearing loss, alters the local cochlear microenvironment and may be a significant contributing factor in cochlear pathogeneses. These studies reveal that chronic low-grade cochlear stress is capable of provoking cochlear immune activity, which could contribute to the generation of clinical symptoms related to changes in hearing function. There is great therapeutic potential in any technique which can mediate the cochlear immune response and decrease cochlear pathogenesis, especially as it pertains to cochlear stresses. In this thesis, evidence for the presence of a low-grade stress-induced cochlear immune activity is disseminated. The findings outlined hint at potential biological targets for future therapeutic strategies aimed at speeding cochlear inflammation resolution and reducing off-target effects of cochlear immune activation.