Abstract
Acoustic overstimulation traumatizes the cochlea, resulting in auditory dysfunction. As a consequence of acoustic injury, the immune system in the cochlea is activated, leading to the production of inflammatory mediators and the infiltration of immune cells. However, the molecular mechanisms responsible for initiating these immune responses remain unclear. Here, we investigate the functional role of Toll-like receptor 4 (Tlr4), a cellular receptor that activates the innate immune system, in the regulation of cochlear responses to acoustic overstimulation. Using a Tlr4 knockout mouse model, we examined how Tlr4 deficiency affects sensory cell pathogenesis, auditory dysfunction and cochlear immune activity. We demonstrate that Tlr4 knockout does not affect sensory cell viability under physiological conditions, but reduces the level of sensory cell damage and cochlear dysfunction after acoustic injury. Together, these findings suggest that Tlr4 promotes sensory cell degeneration and cochlear dysfunction after acoustic injury. Acoustic injury provokes a site-dependent inflammatory response in both the organ of Corti and the tissues of the lateral wall and basilar membrane. Tlr4 deficiency affects these inflammatory responses in a site-dependent manner. In the organ of Corti, loss of Tlr4 function suppresses the production of interleukin 6 (Il6), a pro-inflammatory molecule, after acoustic injury. By contrast, the production of inflammatory mediators, including Il6, persists in the lateral wall and basilar membrane. In addition to immune molecules, Tlr4 knockout inhibits the expression of major histocompatibility complex class II, an antigen-presenting molecule, in macrophages, suggesting that Tlr4 participates in the antigen-presenting function of macrophages after acoustic trauma. Together, these results suggest that Tlr4 regulates multiple aspects of the immune response in the cochlea and contributes to cochlear pathogenesis after acoustic injury.
Highlights
Toll-like receptor 4 (Tlr4) is a receptor for lipopolysaccharide, a structural component of the outer membrane of
We previously demonstrated that Tlr[4] is constitutively expressed in the organ of Corti and that its expression is upregulated after acoustic overstimulation.[19]
This observation suggests that Tlr[4] activation in the organ of Corti exerts a detrimental effect on sensory cells after acoustic injury
Summary
Toll-like receptor 4 (Tlr4) is a receptor for lipopolysaccharide, a structural component of the outer membrane of. We found that Tlr[4] was constitutively expressed in the cochlear sensory epithelium and that acoustic overstimulation caused the gene to be upregulated.[19] Importantly, we found that the change in the expression of Tlr[4] occurred in Deiters cells adjacent to the damaged sensory cells These results suggest that Tlr4-mediated signaling is involved in the cochlear response to sensory cell damage. We found that the loss of Tlr[4] function suppresses the production of major histocompatibility complex class II (MHC II), an antigen presentation-related protein, in macrophages after acoustic injury. These observations suggest that Tlr[4] contributes to multiple aspects of the cochlear immune response to acoustic stress and affects sensory cell survival after acoustic injury
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