Purinergic Signaling and Cochlear Injury-Targeting the Immune System?

Abstract

Hearing impairment is the most common sensory deficit, affecting more than 400 million people worldwide. Sensorineural hearing losses currently lack any specific or efficient pharmacotherapy largely due to the insufficient knowledge of the pathomechanism. Purinergic signaling plays a substantial role in cochlear (patho)physiology. P2 (ionotropic P2X and the metabotropic P2Y) as well as adenosine receptors expressed on cochlear sensory and non-sensory cells are involved mostly in protective mechanisms of the cochlea. They are implicated in the sensitivity adjustment of the receptor cells by a K+ shunt and can attenuate the cochlear amplification by modifying cochlear micromechanics. Cochlear blood flow is also regulated by purines. Here, we propose to comprehend this field with the purine-immune interactions in the cochlea. The role of harmful immune mechanisms in sensorineural hearing losses has been emerging in the horizon of cochlear pathologies. In addition to decreasing hearing sensitivity and increasing cochlear blood supply, influencing the immune system can be the additional avenue for pharmacological targeting of purinergic signaling in the cochlea. Elucidating this complexity of purinergic effects on cochlear functions is necessary and it can result in development of new therapeutic approaches in hearing disabilities, especially in the noise-induced ones.

Hearing impairment and associated morphological changes in pituitary adenylate cyclase activating polypeptide (PACAP)-deficient mice

“…Inflammation 63,64 and angiogenesis 65 are known processes involved in different types of sensorineural hearing loss. In this study, we investigated their role in hearing loss that developed in the absence of endogenous PACAP.…”

Anti-PD-1 Therapy Does Not Influence Hearing Ability in the Most Sensitive Frequency Range, but Mitigates Outer Hair Cell Loss in the Basal Cochlear Region

“…The role of the immune system in hearing and hearing losses is in the focus of auditory research [19,25,26]. Presence of immune cells (e.g., resident macrophages, infiltrating monocytes) [25,27,28] and their activation contributes fundamentally to the maintenance of cochlear homeostasis and function [21,26,[28][29][30][31][32].…”

“…In recent years it has become clear that the inner ear is not an immune privileged organ [15,16]. It contains bone-marrow-derived resident macrophages [17][18][19][20], and insults of the inner ear induces the invasion of the cochlea by monocytes and T cells [20,21]. The released proinflammatory cytokines, chemokines, or reactive oxygen species, by the activated immune cells evoke further cellular infiltration [19,22,23].…”

“…It contains bone-marrow-derived resident macrophages [17][18][19][20], and insults of the inner ear induces the invasion of the cochlea by monocytes and T cells [20,21]. The released proinflammatory cytokines, chemokines, or reactive oxygen species, by the activated immune cells evoke further cellular infiltration [19,22,23]. This cochlear immune system can be involved in either the injury repair processes or the pathogenesis of sensorineural hearing losses [15,16].…”

Postnatal Development of the Subcellular Structures and Purinergic Signaling of Deiters’ Cells along the Tonotopic Axis of the Cochlea

“…ATP is an important extracellular purinergic mediator [20,21,22] in the hearing organ [23,24]. During the prehearing phase of cochlear development, ATP is released by immature supporting cells through hemichannels and it initiates spontaneous Ca 2+ action potential firing in IHCs [7,23,25,26].…”