The Role of Glia in the Peripheral and Central Auditory System Following Noise Overexposure: Contribution of TNF-α and IL-1β to the Pathogenesis of Hearing Loss

Abstract

Repeated noise exposure induces inflammation and cellular adaptations in the peripheral and central auditory system resulting in pathophysiology of hearing loss. In this study, we analyzed the mechanisms by which noise-induced inflammatory-related events in the cochlea activate glial-mediated cellular responses in the cochlear nucleus (CN), the first relay station of the auditory pathway. The auditory function, glial activation, modifications in gene expression and protein levels of inflammatory mediators and ultrastructural changes in glial-neuronal interactions were assessed in rats exposed to broadband noise (0.5–32 kHz, 118 dB SPL) for 4 h/day during 4 consecutive days to induce long-lasting hearing damage. Noise-exposed rats developed a permanent threshold shift which was associated with hair cell loss and reactive glia. Noise-induced microglial activation peaked in the cochlea between 1 and 10D post-lesion; their activation in the CN was more prolonged reaching maximum levels at 30D post-exposure. RT-PCR analyses of inflammatory-related genes expression in the cochlea demonstrated significant increases in the mRNA expression levels of pro- and anti-inflammatory cytokines, inducible nitric oxide synthase, intercellular adhesion molecule and tissue inhibitor of metalloproteinase-1 at 1 and 10D post-exposure. In noise-exposed cochleae, interleukin-1β (IL-1β), and tumor necrosis factor α (TNF-α) were upregulated by reactive microglia, fibrocytes, and neurons at all time points examined. In the CN, however, neurons were the sole source of these cytokines. These observations suggest that noise exposure causes peripheral and central inflammatory reactions in which TNF-α and IL-1β are implicated in regulating the initiation and progression of noise-induced hearing loss.

Engraftment of Human Stem Cell-Derived Otic Progenitors in the Damaged Cochlea

“…It is well known that microglia-macrophages (IBA1-positive cells) are upregulated in response to local cochlear damage induced by ototoxicity or noise exposure. 40,41 For this reason, we analyzed the presence of IBA1-immunopositive cells in ototoxin-damaged animals after engraftment ( Figures 4B-4G). We found that in amikacin-ungrafted control cochlea, a subset of IBA1-immunopositive cells were principally located at the modiolus ( Figure 4E).…”

Macrophage-Mediated Glial Cell Elimination in the Postnatal Mouse Cochlea

“…Macrophages have also been detected in the adult cochlea following cochlear insult (Hirose et al, 2005 ; Lang et al, 2006 ; Sato et al, 2010 ; Kaur et al, 2015 ). Damaged SGNs, auditory glial cells and fibrocytes secrete pro-inflammatory signals that promote the infiltration of macrophages (Bas et al, 2015 ; Fuentes-Santamaría et al, 2017 ). Recent studies have shown that immune-related gene expression increases in the developing auditory nerve (Lu et al, 2011 ; Bank et al, 2012 ; Calton et al, 2014 ).…”

An immortalized microglial cell line (Mocha) derived from rat cochlea

“…Microglia upregulation and neural degeneration persisted for up to 9 months following the initial insult. As further evidence for trauma-mediated microglial activation in the cochlea, an increase in Iba1+ cells co-localized with TNF-alpha and IL1-beta has been reported in the spiral ganglion of noise-exposed rats (Fuentes-Santamaria, et al, 2017). These findings support the hypothesis that microglia may be an important source of pro-inflammatory cytokines, such as IL-1beta, IL-6 and TNF-alpha produced in response to noise damage in the cochlea (Fujioka, et al 2006).…”

“…Microglia have been described in the context of the brain, spinal cord (Galatro, et al, 2017), and retina (Arroba, et al, 2017), but little is known about the biology of microglial cells in the cochlea of the inner ear, a site vulnerable to damage by aging, noise and ototoxic compounds. Very recent studies have begun to address the role of Iba1+ microglia in response to noise exposure in the peripheral and central auditory system of the rat (Fuentes-Santamaria, et al, 2017), but much more characterization is needed. To address this gap in knowledge, we explored the possibility of harvesting and enriching microglia from the rat cochlea with the goal of immortalizing and cultivating them in culture as a novel microglial cell line.…”