The Time Course of Monocytes Infiltration After Acoustic Overstimulation

Shin, Seung Ho; Jung, Jinsei; Park, Haeng Ran; Sim, Nam Suk; Choi, Jae Young; Bae, Seong Hoon

doi:10.3389/fncel.2022.844480

Cited by 10 publications

(18 citation statements)

References 47 publications

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“…We had another cohort of mice whose cochlea were analyzed 8 days following noise exposure and the number of CD45 positive cells were back to baseline levels in the noise alone mouse cohort (Extended View Figure 4). This is in agreement with other studies that showed there was no longer an increased number of immune cells in the cochlea 7-8 days after noise exposure 34,35,76,77 .…”

Section: Discussionsupporting

confidence: 93%

“…We also observed lower amounts of CD68 protein, a macrophage marker, in the cochlea of tizaterkib treated mice compared to noise alone animals. Previous studies have demonstrated that up to 95% of the immune cells in the cochlea are from the monocyte/macrophage origin; therefore, we are proposing that tizaterkib is mainly lowering the number of monocytes that are infiltrating into the cochlea which then differentiate into macrophages 34,35,43,73 . This was supported by the decrease of CD68 protein quantified in the total protein lysates of cochleae of tizaterkib treated mice compared to noise alone mice on day 6 after noise exposure (Figure 8).…”

Section: Discussionmentioning

confidence: 93%

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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: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 93%

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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“…To investigate whether the noise-induced inflammatory state of the cochlea was altered by MR or GR ablation from Sox9 + -supporting cells, we counted Iba1 + immunolabeled cells in the sensory epithelium at 7 dpn. While Iba1 + immunostaining cannot by itself distinguish between resident and infiltrating macrophage-like cells [ 63 , 64 , 65 , 66 ], it is still a useful morphologically-based assessment of potential inflammatory processes occurring in response to noise exposure. We chose 7 dpn because previous research has shown innate immune response increases to its greatest levels in the cochlea after intense (105 dB SPL) noise exposures [ 15 , 16 , 64 , 65 , 67 ] between 3 and 7 dpn and might therefore also be an ideal time to detect differences for innate immune cell presence after the relatively mild (100 dB SPL) noise exposures [ 18 , 19 , 68 ].…”

Section: Resultsmentioning

confidence: 99%

Conditional Ablation of Glucocorticoid and Mineralocorticoid Receptors from Cochlear Supporting Cells Reveals Their Differential Roles for Hearing Sensitivity and Dynamics of Recovery from Noise-Induced Hearing Loss

Barnes

Yee

Vetter

2023

IJMS

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Endogenous glucocorticoids (GC) are known to modulate basic elements of cochlear physiology. These include both noise-induced injury and circadian rhythms. While GC signaling in the cochlea can directly influence auditory transduction via actions on hair cells and spiral ganglion neurons, evidence also indicates that GC signaling exerts effects via tissue homeostatic processes that can include effects on cochlear immunomodulation. GCs act at both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Most cell types in the cochlea express both receptors sensitive to GCs. The GR is associated with acquired sensorineural hearing loss (SNHL) through its effects on both gene expression and immunomodulatory programs. The MR has been associated with age-related hearing loss through dysfunction of ionic homeostatic balance. Cochlear supporting cells maintain local homeostatic requirements, are sensitive to perturbation, and participate in inflammatory signaling. Here, we have used conditional gene manipulation techniques to target Nr3c1 (GR) or Nr3c2 (MR) for tamoxifen-induced gene ablation in Sox9-expressing cochlear supporting cells of adult mice to investigate whether either of the receptors sensitive to GCs plays a role in protecting against (or exacerbating) noise-induced cochlear damage. We have selected mild intensity noise exposure to examine the role of these receptors related to more commonly experienced noise levels. Our results reveal distinct roles of these GC receptors for both basal auditory thresholds prior to noise exposure and during recovery from mild noise exposure. Prior to noise exposure, auditory brainstem responses (ABRs) were measured in mice carrying the floxed allele of interest and the Cre recombinase transgene, but not receiving tamoxifen injections (defined as control (no tamoxifen treatment), versus conditional knockout (cKO) mice, defined as mice having received tamoxifen injections. Results revealed hypersensitive thresholds to mid- to low-frequencies after tamoxifen-induced GR ablation from Sox9-expressing cochlear supporting cells compared to control (no tamoxifen) mice. GR ablation from Sox9-expressing cochlear supporting cells resulted in a permanent threshold shift in mid-basal cochlear frequency regions after mild noise exposure that produced only a temporary threshold shift in both control (no tamoxifen) f/fGR:Sox9iCre+ and heterozygous f/+GR:Sox9iCre+ tamoxifen-treated mice. A similar comparison of basal ABRs measured in control (no tamoxifen) and tamoxifen-treated, floxed MR mice prior to noise exposure indicated no difference in baseline thresholds. After mild noise exposure, MR ablation was initially associated with a complete threshold recovery at 22.6 kHz by 3 days post-noise. Threshold continued to shift to higher sensitivity over time such that by 30 days post-noise exposure the 22.6 kHz ABR threshold was 10 dB more sensitive than baseline. Further, MR ablation produced a temporary reduction in peak 1 neural amplitude one day post-noise. While supporting cell GR ablation trended towards reducing numbers of ribbon synapses, MR ablation reduced ribbon synapse counts but did not exacerbate noise-induced damage including synapse loss at the experimental endpoint. GR ablation from the targeted supporting cells increased the basal resting number of Iba1-positive (innate) immune cells (no noise exposure) and decreased the number of Iba1-positive cells seven days following noise exposure. MR ablation did not alter innate immune cell numbers at seven days post-noise exposure. Taken together, these findings support differential roles of cochlear supporting cell MR and GR expression at basal, resting conditions and especially during recovery from noise exposure.

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“…Recently, our laboratory has shown that ERK1/2 inhibition following noise exposure lowered the number of infiltrating immune cells 7 . Immune cell infiltration and inflammation has been proposed to exacerbate the hearing loss that occurs following cisplatin administration and noise exposure 33,[37][38][39][40] . Lowering MAPK activation following these insults could decrease the number of infiltrating immune cells which could lower the amount of hearing loss.…”

Section: Discussionmentioning

confidence: 99%

KSR1 knockout mouse model demonstrates MAPK pathway’s key role in cisplatin- and noise-induced hearing loss

Ingersoll,

Lutze,

Kelmann

et al. 2023

Preprint

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Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit a large portion of the world population. Here we found that mice devoid of the protein kinase suppressor of RAS 1 (KSR1) in their tissues (germline KO mice) exhibit resistance to both cisplatin- and noise- induced permanent hearing loss compared to their wild-type KSR1 littermates. KSR1 is expressed in the cochlea and is a scaffold protein that brings in proximity the mitogen-activated protein kinase (MAPK) proteins BRAF, MEK and ERK and assists in their activation through a phosphorylation cascade induced by both cisplatin and noise insults in the cochlear cells. Deleting the KSR1 protein tempered down the MAPK phosphorylation cascade in the cochlear cells following both cisplatin and noise insults and conferred hearing protection of up to 30 dB SPL in three tested frequencies in mice. Treatment with dabrafenib, an FDA- approved oral BRAF inhibitor, downregulated the MAPK kinase cascade and protected the KSR1 wild-type mice from both cisplatin- and noise-induced hearing loss. Dabrafenib treatment did not enhance the protection of KO KSR1 mice, as excepted, providing evidence dabrafenib works primarily through the MAPK pathway. Thus, either elimination of the KSR1 gene expression or drug inhibition of the MAPK cellular pathway in mice resulted in profound protection from both cisplatin- and noise-induce hearing loss. Inhibition of the MAPK pathway, a cellular pathway that responds to damage in the cochlear cells, can prove a valuable strategy to protect and treat hearing loss.Significance StatementTen percent of the world population suffers from hearing loss but this impairment may be preventable. We show that mice devoid of the KSR1 protein (KO) exhibit resistance to cisplatin- and noise-induced permanent hearing loss compared to wild-type littermates that harbor the protein. Removing KSR1 tempers down the MAPK phosphorylation cascade of BRAF-MEK-ERK induced in the cochlea following cisplatin and noise insults. Treatment of KSR1 wild-type mice following cisplatin or noise with an FDA-approved BRAF inhibitor, dabrafenib, protected the hearing and, importantly, did not confer additional protection to the KO KSR1 mice. Hence, the MAPK pathway has a unique role in responding to cochlear damage, and removing KSR1 gene expression or drug inhibition of the pathway results in hearing protection.

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The Time Course of Monocytes Infiltration After Acoustic Overstimulation

Cited by 10 publications

References 47 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

Conditional Ablation of Glucocorticoid and Mineralocorticoid Receptors from Cochlear Supporting Cells Reveals Their Differential Roles for Hearing Sensitivity and Dynamics of Recovery from Noise-Induced Hearing Loss

KSR1 knockout mouse model demonstrates MAPK pathway’s key role in cisplatin- and noise-induced hearing loss

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