Inner ear immunity

Keithley, Elizabeth M.

doi:10.1016/j.heares.2022.108518

Cited by 22 publications

(16 citation statements)

References 143 publications

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“…Modulating the number of immune cells in the cochlea following noise insult could lead to protection form NIHL [54][55][56] . We exposed the mice to the same noise exposure as before (100 dB for 2 hours at 8-16 kHz octave band) and treated mice with carrier or 0.5 mg/kg tizaterkib for three days, twice a day.…”

Section: Tizaterkib Treated Mice Have Significantly Less Immune Cells...mentioning

confidence: 99%

ERK1/2 Inhibition Alleviates Noise-Induced Hearing Loss While Tempering Down the Immune Response

Lutze,

Ingersoll,

Thotam

et al. 2023

Preprint

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Noise-induced hearing loss (NIHL) is a major cause of hearing impairment, yet no FDA-approved drugs exist to prevent it. Targeting the mitogen activated protein kinase (MAPK) cellular pathway has emerged as a promising approach to attenuate NIHL. Tizaterkib is an orally bioavailable, highly specific ERK1/2 inhibitor, currently in Phase-1 anticancer clinical trials. Here, we tested tizaterkib's efficacy against permanent NIHL in mice at doses equivalent to what humans are currently prescribed in clinical trials. The drug given orally 24 hours after noise exposure, protected an average of 20-25 dB SPL in three frequencies, in female and male mice, had a therapeutic window >50, and did not confer additional protection to KSR1 genetic knockout mice, showing the drug works through the MAPK pathway. Tizaterkib shielded from noise-induced cochlear synaptopathy, and a 3-day, twice daily, treatment with the drug was the optimal determined regimen. Importantly, tizaterkib was shown to decrease the number of CD45 and CD68 positive immune cells in the cochlea following noise exposure, which could be part of the protective mechanism of MAPK inhibition.

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Section: Tizaterkib Treated Mice Have Significantly Less Immune Cells...mentioning

confidence: 99%

ERK1/2 Inhibition Alleviates Noise-Induced Hearing Loss While Tempering Down the Immune Response

Lutze,

Ingersoll,

Thotam

et al. 2023

Preprint

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“…Knowledge of the immune environment within the cochlea has been extended in recent years. In the normal mammalian cochlea, a heterogenous mixture of B-cells, T-cells, macrophages, natural killer cells, and neutrophils has been identi ed (51). Studies of the human cochlea have detected macrophages (52)(53)(54), CD4 and CD8 T-cells (55), and B-cells (56) in various cochlear compartments.…”

Section: Discussionmentioning

confidence: 99%

Hearing loss and its association with the proteome of perilymph, cerebrospinal fluid, and tumor tissue in patients with vestibular schwannoma

Rasmussen,

Li,

Laurel

et al. 2024

Preprint

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This study examined the association between hearing loss in sporadic vestibular schwannoma patients and the proteome of perilymph (PL), cerebrospinal fluid (CSF), and vestibular schwannoma. Intraoperative sampling of PL and of CSF, and biopsy of vestibular schwannoma tissue, was performed in 32, 32, and 20 patients with vestibular schwannoma, respectively. Perilymph and CSF in three patients with meningioma and normal hearing were also sampled. The proteomes were identified by liquid chromatography coupled to high-resolution tandem mass spectrometry. Preoperative hearing function of the patients was evaluated with pure tone audiometry, with mean values at frequencies of 500, 1000, 2000, and 4000 Hz (PTA4) in the tumor-affected ear used to delineate three hearing groups. Analysis of the PL samples revealed significant upregulation of complement factor H-related protein 2 (CFHR2) in patients with severe to profound hearing loss after false discovery rate correction. Pathway analysis of biofunctions revealed higher activation scores in the severe/profound hearing loss group of leukocyte migration, viral infection, and migration of cells in PL. Upregulation of CFHR2 and activation of these pathways indicate chronic inflammation in the cochlea of vestibular schwannoma patients with severe to profound hearing loss compared with patients with normal hearing or mild hearing loss.

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“…From this, there can be extensive water flow radiating outward and along the capillary path. What is not absorbed by the venous system may be resorbed by lymphatic vessels that have been reported in the spiral ligament (Keithley, 2022 ), although the evidence for lymphatic vessels in the spiral ligament is limited. The interior of the tightly sealed strial space (see below) may be limited by this standard arrangement, in that (1) longitudinal water flow within the stria may not be permissible, (2) the post-capillary venules of the inferior ligament may be too far away, (3) the largely uncharacterized lymphatics of the spiral ligament may be too remote and may have poor access to intrastrial fluid, and (4) the post-capillary venules in the ligament have been found to have an elevated hydrostatic pressure, which could discourage re-entry of water and waste products (Shaddock et al, 1985 ).…”

Section: What Cells and Tissues Do Strial Capillaries Support?mentioning

confidence: 99%

A critical evaluation of “leakage” at the cochlear blood-stria-barrier and its functional significance

Ohlemiller,

Dwyer,

Henson

et al. 2024

Front. Mol. Neurosci.

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The blood-labyrinth-barrier (BLB) is a semipermeable boundary between the vasculature and three separate fluid spaces of the inner ear, the perilymph, the endolymph and the intrastrial space. An important component of the BLB is the blood-stria-barrier, which shepherds the passage of ions and metabolites from strial capillaries into the intrastrial space. Some investigators have reported increased “leakage” from these capillaries following certain experimental interventions, or in the presence of inflammation or genetic variants. This leakage is generally thought to be harmful to cochlear function, principally by lowering the endocochlear potential (EP). Here, we examine evidence for this dogma. We find that strial capillaries are not exclusive, and that the asserted detrimental influence of strial capillary leakage is often confounded by hair cell damage or intrinsic dysfunction of the stria. The vast majority of previous reports speculate about the influence of strial vascular barrier function on the EP without directly measuring the EP. We argue that strial capillary leakage is common across conditions and species, and does not significantly impact the EP or hearing thresholds, either on evidentiary or theoretical grounds. Instead, strial capillary endothelial cells and pericytes are dynamic and allow permeability of varying degrees in response to specific conditions. We present observations from mice and demonstrate that the mechanisms of strial capillary transport are heterogeneous and inconsistent among inbred strains.

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Inner ear immunity

Cited by 22 publications

References 143 publications

ERK1/2 Inhibition Alleviates Noise-Induced Hearing Loss While Tempering Down the Immune Response

ERK1/2 Inhibition Alleviates Noise-Induced Hearing Loss While Tempering Down the Immune Response

Hearing loss and its association with the proteome of perilymph, cerebrospinal fluid, and tumor tissue in patients with vestibular schwannoma

A critical evaluation of “leakage” at the cochlear blood-stria-barrier and its functional significance

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