Role of innate immune function in the neurobiological substrates of hearing loss

Abstract

Macrophages are the most abundant immune cell within the cochlea. Their role in the pathophysiology of hearing loss is not well understood despite a body of work studying human and animal cochleae. The aim of this research was to investigate the role of innate immune function in the cochlea. A multi-method approach, using analysis of mouse and human tissue to investigate the role of macrophages in cochlear health, was carried out. The current evidence for the distribution, morphology and function of macrophages following acute and chronic cochlear insults was reviewed. Findings support the hypothesis that cochlear macrophages contribute to the trajectory of hearing loss through macrophage activation. The effects of chronic middle ear inflammation were studied using the Junbo mouse model, a mutation that results in changes characteristic of otitis media. Increased macrophage activation and Il-1β expression was observed in the cochlea and middle ear of Junbo mice inferring that middle ear inflammation caused increased macrophage activation across regions of the inner ear, or cochlea. A method to analyse fibrotic tissue on explanted cochlear implants was developed. Histological analysis revealed an aberrant, unresolved wound healing response with evidence of ongoing inflammation and proliferation, on an implant 10 months after implantation. Cochlear implantation in the mouse was established as the basis of a model system for the experimental study of tissue responses to cochlear implantation. This model enables a combination of tissue analysis methods, alongside micro-computed tomography imaging, to investigate the tissue response and factors which influence the response. This work has consolidated the evidence for cochlear macrophages as a key cell population in cochlear health, and that they may have a role in hearing loss. This is important as they may be amenable to manipulation that alters the course of hearing loss. It has established that an existing, partially characterised, mouse model warrants more detailed study that may be translationally relevant in understanding the consequence of early life middle ear inflammation. It reports the first published evidence for immune responses to an implant in a person undergoing subsequent reimplantation, and establishes a pipeline for human explant tissue analysis that will lead to new understanding of poor hearing performance with a cochlear implant. This research advances our understanding of the innate immune mechanisms involved in cochlear health and identifies a new putative therapeutic target that may lead to improved hearing outcomes with a cochlear implant.

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ORCID for Kate Hough: orcid.org/0000-0002-5160-2517

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