The Contribution of Immune Infiltrates to Ototoxicity and Cochlear Hair Cell Loss

Abstract

Cells of the immune system have been shown to infiltrate the cochlea after acoustic trauma or ototoxic drug treatment; however, the contribution of the immune system to hair cell loss in the inner ear is incompletely understood. Most studies have concentrated on the immediate innate response to hair cell damage using CD45 as a broad marker for all immune cells. More recent studies have used RNA sequencing, GeneChip arrays and quantitative PCR to analyze gene expression in the entire cochlea after auditory trauma, leading to a better understanding of the chemokines and cytokines that attract immune cells to the cochlea. Immune suppression by blocking cytokines or immune receptors has been proven to suppress hair cell damage. However, it is now understood that not all immune cells are detrimental to the cochlea. CX3CR1+ resident macrophages protect hair cells from damage mediated by infiltrating immune cells. Systemically, the immune response is associated with both protection and pathology, and it has been implicated in the regeneration of certain tissues after injury. This review focuses on the studies of immune cells in various models of hearing loss and highlights the steps that can be taken to elucidate the connection between the immune response and hearing loss. The interplay between the immune system and tissues that were previously thought to be immune privileged, such as the cochlea, is an emerging research field, to which additional studies of the immune component of the cochlear response to injury will make an important contribution.

Resolution of Cochlear Inflammation: Novel Target for Preventing or Ameliorating Drug-, Noise- and Age-related Hearing Loss

“…The nature of the immune cells infiltrating the cochlea has been discussed in a recent review (Wood and Zuo, 2017), and will not be addressed here. The infiltrating cells transform into activated macrophages and express pro-inflammatory proteins (Yang et al, 2015).…”

Macrophages in Noise-Exposed Cochlea: Changes, Regulation and the Potential Role

“…Their properties and functions are mainly determined by local environmental factors, which allows them to adapt highly to the needs of their anatomical niche. Studies have shown that after noise exposure, the distribution, phenotype, and the number of cochlear macrophages have significantly changed, and the local environmental factors that shape macrophage differentiation and behavior are also drastically altered, which supports the concept that macrophages play a vital role in cochlear response to acoustic injury [3,5]. However, the exact role of these immune cells in the cochlea after noise exposure remains unknown.…”

“…However, the cellular and molecular mechanisms underlying NIHL have not been fully clarified, therefore, clinically NIHL lacks effective therapeutic methods. Recently, inflammation and immune response have been increasingly recognized as important pathophysiological mechanisms underlying irreparable or reparable damage to hair cells and neurons after acoustic injury [1][2][3]. As the major professional immune cells in the cochlea, macrophages contribute to the inflammation, repair, and homeostasis, playing a critical role in local cochlear immunity [4].…”

Necroptosis and apoptosis contribute to cisplatin and aminoglycoside ototoxicity

“…A hair cell with necroptotic response thus would only make sense if the inner ear was not “immune privileged” as historically assumed but was capable of mounting a significant immunological response. In fact, more recent studies suggest that the resolution of ototoxic insults is aided by immune cells infiltrating into the inner ear (Kaur, 2015; Kaur et al, 2015, 2018; Francis and Cunningham, 2017; Mizushima et al, 2017; Wood and Zuo, 2017; Barald et al, 2018; Liu et al, 2018). Such immune activity, beneficial under normal circumstances, might become counterproductive when ototoxins overwhelm the system, creating a massive, detrimental immune response.…”