Aging Rewrites the Immune Landscape of the Cochlear Spiral Ganglion in Mice

The inner ear has long been treated as a quiet, immune-privileged organ, but a new study in GeroScience suggests that aging stirs up a surprising amount of immunological activity deep inside the hearing nerve. Researchers at Seoul National University mapped immune- and glia-associated marker expression in the cochlear spiral ganglion of young and aged mice and found that specific populations of microglia-like cells and satellite glial cells carried markedly more immune markers in aged animals. A short course of a drug that depletes macrophages and microglia reduced the density of several of these marker-positive populations, offering a first descriptive look at how the immune microenvironment of the hearing nerve changes with age.

Age-related hearing loss and noise-induced hearing loss are the two most common forms of acquired auditory impairment, yet the immune biology underlying them has remained poorly understood. The cochlea was traditionally regarded as an immune-privileged site with limited immune cell activity, but accumulating evidence indicates that it actively engages in immune and inflammatory processes. What has been missing is a systematic comparison of the immune cells involved in each condition, and any indication of whether that immune environment can be pharmacologically modified.

The first were Iba1-positive microglia-like cells, resident macrophage-like cells regulated by colony-stimulating factor 1 receptor (CSF1R) signaling. The second were satellite glial cells, peripheral glial cells that wrap around neuronal cell bodies and support their structural integrity and metabolic homeostasis. Satellite glial cells have not traditionally been considered immune-competent, and their role in cochlear immune remodeling had not previously been examined.

The study used double immunofluorescence staining for the markers Iba1, Tmem119, Sox2, and CD74 across four groups of mice: young controls, young mice with noise-induced hearing loss, aged mice treated with a vehicle, and aged mice treated with PLX5622, a CSF1R inhibitor known to deplete microglia and macrophages. Young mice were 8-week-old C57BL/6 animals, while the aged group consisted of 24-month-old CX3CR1-positive-GFP transgenic mice on a C57BL/6 background. Immunofluorescence quantification was performed in three animals per group, with cell counts averaged across three spiral ganglion sections per animal before statistical comparison.

The results divided cleanly along age lines. In young mice, noise exposure sufficient to produce measurable behavioral hearing changes did not significantly alter total Iba1-positive cell density or Iba1/CD74 co-expression in the spiral ganglion compared with controls. The noise protocol exposed mice to broadband white noise at 115 decibels for three hours per day over two consecutive days, and the animals were sacrificed one to two months later, a window chosen to capture the chronic phase of injury rather than the acute response. The authors caution that an earlier, transient immune reaction in the days immediately after noise exposure cannot be excluded by this design and would require a dedicated time-course study.

Aged mice told a different story. Compared with young controls, aged vehicle-treated animals showed a statistically significant increase in total Iba1-positive cell density and in the densities of Iba1/Tmem119 double-positive, Iba1/CD74 double-positive, and Sox2/CD74 double-positive cells. Tmem119 is a homeostatic marker of central nervous system microglia, and CD74 is a molecule involved in MHC class II antigen presentation that also serves as a receptor for macrophage migration inhibitory factor. A similar upward trend appeared for Sox2/Tmem119 co-expression, but it did not reach statistical significance after correction for multiple comparisons, and the authors describe it as a preliminary trend rather than confirmed evidence of a distinct cell state.

Treatment with PLX5622, delivered through drinking water at 2,400 parts per million for seven consecutive days, significantly reduced total Iba1-positive, Iba1/Tmem119-positive, Iba1/CD74-positive, and Sox2/CD74-positive cell densities in the aged animals. Cochlear whole-mount preparations from the reporter mice confirmed a marked depletion of GFP-positive macrophages in the middle turn of the cochlea. The dose was doubled from an initial 1,200 parts per million after pilot trials showed inadequate macrophage depletion in the aged cochlea at the lower concentration.

Behavioral testing added context but also complexity. Acoustic startle responses and prepulse inhibition confirmed that noise exposure reduced auditory-related sensorimotor responsiveness in young mice. In aged animals, the startle amplitude decrease after PLX5622 did not survive correction for multiple comparisons across the ten stimulus intensities tested, and a numerical drop in prepulse inhibition was driven by a single statistical outlier. In the novel object recognition test, the discrimination index decreased significantly after treatment, while the Y-maze spontaneous alternation rate did not change, although distance moved and velocity increased. The authors interpret these mixed findings cautiously, noting they may reflect task-specific effects on arousal, exploration, or locomotion rather than a clear cognitive consequence of macrophage depletion.

The team also mined publicly available single-cell RNA-sequencing data through the gEAR portal to place their marker findings in context. These analyses showed that Tmem119 expression in the cochlea is not restricted to microglia or macrophages but is also detected in Nudt4-positive fibrocyte-like supporting stromal cells, and that CD74 expression is broadly maintained across supporting and glial cell populations, appearing in satellite glial cells by five months of age. This suggests that marker upregulation in Sox2-positive satellite glial cells may reflect a broader aging-associated shift in glial gene expression rather than the acquisition of a bona fide microglial identity.

The authors are explicit about the limits of their work. Age and genotype were confounded, because the young mice were C57BL/6 while the aged mice were CX3CR1 reporter animals, so Cx3cr1 haploinsufficiency cannot be formally excluded as a contributor. PLX5622 acts on CSF1R-expressing myeloid cells throughout the body, so the observed changes could reflect local cochlear macrophage depletion, indirect systemic effects, or direct effects on other cell populations. The sample size for immunofluorescence was small, cell counting was two-dimensional rather than stereological, observer blinding was not performed, and the study relied on startle-based behavioral measures rather than direct electrophysiological assessments of hearing threshold. Changes in marker immunoreactivity, the authors stress, do not by themselves establish phenotypic conversion or functional remodeling, and the data do not show that CSF1R inhibition is a therapeutic strategy for hearing loss. What the study does provide is a descriptive foundation: coordinated, age-associated changes in immune- and glia-associated marker expression in the cochlear spiral ganglion, several of which respond to CSF1R inhibition, and a clear set of hypotheses about MIF-CD74 signaling and local versus systemic drug effects that now await direct testing.

Subject of Research: Age-associated changes in microglia-like and satellite glial cell immune markers in the mouse cochlear spiral ganglion and their modulation by CSF1R inhibition

Article Title: Age-associated changes in microglia-like and satellite glial cell markers in the cochlear spiral ganglion

Article References: Park, B., Jeon, J. C., Kim, D. E., Park, N., & Kim, S. Y. (2026). Age-associated changes in microglia-like and satellite glial cell markers in the cochlear spiral ganglion. GeroScience. https://doi.org/10.1007/s11357-026-02617-w

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02617-w

Keywords: age-related hearing loss, cochlea, spiral ganglion, microglia, satellite glial cells, CD74, Tmem119, Iba1, Sox2, PLX5622, CSF1R inhibitor, immunofluorescence