In the sensory epithelium, macrophages have been identified on the scala tympani side of the basilar membrane. These basilar membrane macrophages are the spatially closest immune cells to sensory cells and are able to directly respond to and influence sensory cell pathogenesis. While basilar membrane macrophages have been studied in acute cochlear stresses, their behavior in response to chronic sensory cell degeneration is largely unknown. Here we report a systematic observation of the variance in phenotypes, the changes in morphology and distribution of basilar membrane tissue macrophages in different age groups of C57BL/6J mice, a mouse model of age-related sensory cell degeneration. This study reveals that mature, fully differentiated tissue macrophages, not recently infiltrated monocytes, are the major macrophage population for immune responses to chronic sensory cell death. These macrophages display dynamic changes in their numbers and morphologies as age increases, and the changes are related to the phases of sensory cell degeneration. Notably, macrophage activation precedes sensory cell pathogenesis, and strong macrophage activity is maintained until sensory cell degradation is complete. Collectively, these findings suggest that mature tissue macrophages on the basilar membrane are a dynamic group of cells that are capable of vigorous adaptation to changes in the local sensory epithelium environment influenced by sensory cell status.

The cochlea has an immune environment dominated by macrophages under resting conditions. When stressed, circulating monocytes enter the cochlea. These immune mediators, along with cochlear resident cells, organize a complex defense response against pathological challenges. Since the cochlea has minimal exposure to pathogens, most inflammatory conditions in the cochlea are sterile. Although the immune response is initiated for the protection of the cochlea, off-target effects can cause collateral damage to cochlear cells. A better understanding of cochlear immune capacity and regulation would therefore lead to development of new therapeutic treatments. Over the past decade, there have been many advances in our understanding of cochlear immune capacity. In this review, we provide an update and overview of the cellular components of cochlear immune capacity with a focus on macrophages in mammalian cochleae. We describe the composition and distribution of immune cells in the cochlea and suggest that phenotypic and functional characteristics of macrophages have site-specific diversity. We also highlight the response of immune cells to acute and chronic stresses and comment on the potential function of immune cells in cochlear homeostasis and disease development. Finally, we briefly review potential roles for cochlear resident cells in immune activities of the cochlea.

Inflammation is a complex biological response to harmful stimuli including infection, tissue damage, and toxins. Thus, it is not surprising that cochlear damage by noise includes an inflammatory component. One mechanism by which inflammation is generated by tissue damage is the activation of damage-associated molecular patterns (DAMPs). Many of the cellular receptors for DAMPS, including Toll-like receptors, NOD-like receptors, and DNA receptors, are also receptors for pathogens, and function in the innate immune system. DAMP receptors are known to be expressed by cochlear cells, and binding of molecules released by damaged cells to these receptors result in the activation of cell stress pathways. This leads to the generation of pro-inflammatory cytokines and chemokines that recruit pro-inflammatory leukocytes. Extensive evidence indicates pro-inflammatory cytokines including TNF alpha and interleukin 1 beta, and chemokines including CCL2, are induced in the cochlea after noise exposure. The recruitment of macrophages into the cochlea has also been demonstrated. These provide substrates for noise damage to be enhanced by inflammation. Evidence is provided by the effectiveness of anti-inflammatory drugs in ameliorating noise-induced hearing loss. Involvement of inflammation provides a wide variety of additional anti-inflammatory and pro-resolution agents as potential pharmacological interventions in noise-induced hearing loss.

Noise exposure producing temporary threshold shifts (TTS) has been demonstrated to cause permanent changes to cochlear physiology and hearing function. Several explanations have been purported to underlie these long-term changes in cochlear function, such as damage to sensory cell stereocilia and synaptic connections between sensory cells and their innervation by spiral ganglion neurons, and demyelination of the auditory nerve. Though these structural defects have been implicated in hearing difficulty, cochlear responses to this stress damage remains poorly understood. Here, we report the activation of the cochlear immune system following exposure to lower level noise (LLN) that causes only TTS. Using multiple morphological, molecular and functional parameters, we assessed the responses of macrophages, the primary immune cell population in the cochlea, to the LLN exposure. This study reveals that a LLN that causes only TTS increases the macrophage population in cochlear regions immediately adjacent to sensory cells and their innervations. Many of these cells acquire an activated morphology and express the immune molecules CCL2 and ICAM1 that are important for macrophage inflammatory activity and adhesion. However, LLN exposure reduces macrophage phagocytic ability. While the activated morphology of cochlear macrophages reverses, the complete recovery is not achieved 2 months after the LLN exposure. Taken together, these observations clearly implicate the cochlear immune system in the cochlear response to LLN that causes no permanent threshold change.

The cochlea contains macrophages. These cells participate in inflammatory responses to cochlear pathogenesis. However, it is not clear how and when these cells populate the cochlea during postnatal development. The current study aims to determine the postnatal development of cochlear macrophages with the focus on macrophage development in the organ of Corti and the basilar membrane. Cochleae were collected from C57BL/6J mice at ages of postnatal day (P) 1 to P21, as well as from mature mice (1-4 months). Macrophages were identified based on their expression of F4/80 and Iba1, as well as their unique morphologies. Two sets of macrophages were identified in the regions of the organ of Corti and the basilar membrane. One set resides on the scala tympani side of the basilar membrane. These cells have a round shape at P1 and start to undergo site-specific differentiation at P4. Apical macrophages adopt a dendritic shape. Middle and basal macrophages take on an irregular shape with short projections. Basal macrophages further differentiate into an amoeboid shape. The other set of macrophages resides above the basilar membrane, either beneath the cells of the organ of Corti or along the spiral vessel of the basilar membrane. As the sensory epithelium matures, these cells undergo developmental death with the phenotypes of apoptosis. Macrophages are also identified in the spiral ligament, spiral limbus, and neural regions. Their numbers decrease during postnatal development. Together, these results suggest a dynamic rearrangement of the macrophage population during postnatal cochlear development.