scholarly journals Local Macrophage-Related Immune Response Is Involved in Cochlear Epithelial Damage in Distinct Gjb2-Related Hereditary Deafness Models

2021 ◽  
Vol 8 ◽  
Author(s):  
Kai Xu ◽  
Sen Chen ◽  
Le Xie ◽  
Yue Qiu ◽  
Xue Bai ◽  
...  
Keyword(s):  
Immune Response ◽  
Spiral Ganglion ◽  
Null Model ◽  
Outer Hair Cells ◽  
Inflammatory Factors ◽  
Null Mouse ◽  
Cell Degeneration ◽  
Hereditary Deafness ◽  
Macrophage Recruitment ◽  
Ganglion Neurons

The macrophage-related immune response is an important component of the cochlear response to different exogenous stresses, including noise, ototoxic antibiotics, toxins, or viral infection. However, the role of the immune response in hereditary deafness caused by genetic mutations is rarely explored. GJB2, encoding connexin 26 (Cx26), is the most common deafness gene of hereditary deafness. In this study, two distinct Cx26-null mouse models were established to investigate the types and underlying mechanisms of immune responses. In a systemic Cx26-null model, macrophage recruitment was observed, associated with extensive cell degeneration of the cochlear epithelium. In a targeted-cell Cx26-null model, knockout of Cx26 was restricted to specific supporting cells (SCs), which led to preferential loss of local outer hair cells (OHCs). This local OHC loss can also induce a macrophage-related immune response. Common inflammatory factors, including TNF-α, IL-1β, Icam-1, Mif, Cx3cr1, Tlr4, Ccl2, and Ccr2, did not change significantly, while mRNA of Cx3cl1 was upregulated. Quantitative immunofluorescence showed that the protein expression of CX3CL1 in Deiters cells, a type of SC coupled with OHCs, increased significantly after OHC death. OHC loss caused the secondary death of spiral ganglion neurons (SGNs), while the remaining SGNs expressed high levels of CX3CL1 with infiltrated macrophages. Taken together, our results indicate that CX3CL1 signaling regulates macrophage recruitment and that enhancement of macrophage antigen-presenting function is associated with cell degeneration in Cx26-null mice.

scholarly journals Gpr125 Marks Distinct Cochlear Cell Types and Is Dispensable for Cochlear Development and Hearing

2021 ◽  
Vol 9 ◽  
Author(s):  
Haiying Sun ◽  
Tian Wang ◽  
Patrick J. Atkinson ◽  
Sara E. Billings ◽  
Wuxing Dong ◽  
...  
Keyword(s):  
Spiral Ganglion ◽  
Cell Types ◽  
Supporting Cell ◽  
Outer Hair Cells ◽  
Sensory Cells ◽  
Convergent Extension ◽  
Multiple Organs ◽  
Auditory Physiology ◽  
Cochlear Development ◽  
Ganglion Neurons

The G protein-coupled receptor (GPR) family critically regulates development and homeostasis of multiple organs. As a member of the GPR adhesion family, Gpr125 (Adgra3) modulates Wnt/PCP signaling and convergent extension in developing zebrafish, but whether it is essential for cochlear development in mammals is unknown. Here, we examined the Gpr125lacZ/+ knock-in mice and show that Gpr125 is dynamically expressed in the developing and mature cochleae. From embryonic day (E) 15.5 to postnatal day (P) 30, Gpr125-β-Gal is consistently expressed in the lesser epithelial ridge and its presumed progenies, the supporting cell subtypes Claudius cells and Hensen’s cells. In contrast, Gpr125-β-Gal is expressed transiently in outer hair cells, epithelial cells in the lateral cochlear wall, interdental cells, and spiral ganglion neurons in the late embryonic and early postnatal cochlea. In situ hybridization for Gpr125 mRNA confirmed Gpr125 expression and validated loss of expression in Gpr125lacZ/lacZ cochleae. Lastly, Gpr125lacZ/+ and Gpr125lacZ/lacZ cochleae displayed no detectable loss or disorganization of either sensory or non-sensory cells in the embryonic and postnatal ages and exhibited normal auditory physiology. Together, our study reveals that Gpr125 is dynamically expressed in multiple cell types in the developing and mature cochlea and is dispensable for cochlear development and hearing.

scholarly journals 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

2020 ◽  
Vol 21 (18) ◽  
pp. 6701
Author(s):  
Judit Szepesy ◽  
Gabriella Miklós ◽  
János Farkas ◽  
Dániel Kucsera ◽  
Zoltán Giricz ◽  
...  
Keyword(s):  
Outer Hair Cell ◽  
Checkpoint Inhibitors ◽  
Spiral Ganglion ◽  
Auditory Brainstem ◽  
Outer Hair Cells ◽  
Antibody Treatment ◽  
High Frequency Region ◽  
Age Related ◽  
Brainstem Response ◽  
Ganglion Neurons

The administration of immune checkpoint inhibitors (ICIs) often leads to immune-related adverse events. However, their effect on auditory function is largely unexplored. Thorough preclinical studies have not been published yet, only sporadic cases and pharmacovigilance reports suggest their significance. Here we investigated the effect of anti-PD-1 antibody treatment (4 weeks, intraperitoneally, 200 μg/mouse, 3 times/week) on hearing function and cochlear morphology in C57BL/6J mice. ICI treatment did not influence the hearing thresholds in click or tone burst stimuli at 4–32 kHz frequencies measured by auditory brainstem response. The number and morphology of spiral ganglion neurons were unaltered in all cochlear turns. The apical-middle turns (<32 kHz) showed preservation of the inner and outer hair cells (OHCs), whilst ICI treatment mitigated the age-related loss of OHCs in the basal turn (>32 kHz). The number of Iba1-positive macrophages has also increased moderately in this high frequency region. We conclude that a 4-week long ICI treatment does not affect functional and morphological integrity of the inner ear in the most relevant hearing range (4–32 kHz; apical-middle turns), but a noticeable preservation of OHCs and an increase in macrophage activity appeared in the >32 kHz basal part of the cochlea.

scholarly journals Developmental Changes in Peripherin-eGFP Expression in Spiral Ganglion Neurons

2021 ◽  
Vol 15 ◽  
Author(s):  
Karen L. Elliott ◽  
Jennifer Kersigo ◽  
Jeong Han Lee ◽  
Israt Jahan ◽  
Gabriela Pavlinkova ◽  
...  
Keyword(s):  
Hair Cells ◽  
Spiral Ganglion ◽  
Outer Hair Cells ◽  
Egfp Expression ◽  
Spiral Ganglion Neurons ◽  
Type Ii ◽  
Neuronal Types ◽  
Type Ii Cell ◽  
Reliable Marker ◽  
Ganglion Neurons

The two types of spiral ganglion neurons (SGNs), types I and II, innervate inner hair cells and outer hair cells, respectively, within the mammalian cochlea and send another process back to cochlear nuclei in the hindbrain. Studying these two neuronal types has been made easier with the identification of unique molecular markers. One of these markers, peripherin, was shown using antibodies to be present in all SGNs initially but becomes specific to type II SGNs during maturation. We used mice with fluorescently labeled peripherin (Prph-eGFP) to examine peripherin expression in SGNs during development and in aged mice. Using these mice, we confirm the initial expression of Prph-eGFP in both types I and II neurons and eventual restriction to only type II perikarya shortly after birth. However, while Prph-eGFP is uniquely expressed within type II cell bodies by P8, both types I and II peripheral and central processes continue to express Prph-eGFP for some time before becoming downregulated. Only at P30 was there selective type II Prph-eGFP expression in central but not peripheral processes. By 9 months, only the type II cell bodies and more distal central processes retain Prph-eGFP expression. Our results show that Prph-eGFP is a reliable marker for type II SGN cell bodies beyond P8; however, it is not generally a suitable marker for type II processes, except for central processes beyond P30. How the changes in Prph-eGFP expression relate to subsequent protein expression remains to be explored.

scholarly journals Toward Cochlear Therapies

2018 ◽  
Vol 98 (4) ◽  
pp. 2477-2522 ◽  
Author(s):  
Jing Wang ◽  
Jean-Luc Puel
Keyword(s):  
Spiral Ganglion ◽  
Industrialized Countries ◽  
Cell Degeneration ◽  
Age Related ◽  
Causative Factors ◽  
Sensorineural Hearing Impairment ◽  
Endogenous Protection ◽  
Mechanosensory Hair Cells ◽  
Ganglion Neurons ◽  
Age Related Hearing Loss

Sensorineural hearing impairment is the most common sensory disorder and a major health and socio-economic issue in industrialized countries. It is primarily due to the degeneration of mechanosensory hair cells and spiral ganglion neurons in the cochlea via complex pathophysiological mechanisms. These occur following acute and/or chronic exposure to harmful extrinsic (e.g., ototoxic drugs, noise...) and intrinsic (e.g., aging, genetic) causative factors. No clinical therapies currently exist to rescue the dying sensorineural cells or regenerate these cells once lost. Recent studies have, however, provided renewed hope, with insights into the therapeutic targets allowing the prevention and treatment of ototoxic drug- and noise-induced, age-related hearing loss as well as cochlear cell degeneration. Moreover, genetic routes involving the replacement or corrective editing of mutant sequences or defected genes are showing promise, as are cell-replacement therapies to repair damaged cells for the future restoration of hearing in deaf people. This review begins by recapitulating our current understanding of the molecular pathways that underlie cochlear sensorineural damage, as well as the survival signaling pathways that can provide endogenous protection and tissue rescue. It then guides the reader through to the recent discoveries in pharmacological, gene and cell therapy research towards hearing protection and restoration as well as their potential clinical application.

Differential Expression of Bcl-2 in the Cochlea and Auditory Cortex of a Mouse Model of Age-Related Hearing Loss

2016 ◽  
Vol 21 (5) ◽  
pp. 326-332 ◽  
Author(s):  
Qiuhong Huang ◽  
Hao Xiong ◽  
Haidi Yang ◽  
Yongkang Ou ◽  
Zhigang Zhang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Mouse Model ◽  
Auditory Cortex ◽  
Hair Cells ◽  
Spiral Ganglion ◽  
Outer Hair Cells ◽  
Protective Effects ◽  
Age Related ◽  
Ganglion Neurons ◽  
Age Related Hearing Loss

Bcl-2, the first gene shown to be involved in apoptosis, is a potent regulator of cell survival and known to have protective effects against a variety of age-related diseases. However, the possible relationship between hearing and Bcl-2 expression in the cochlea or auditory cortex of C57BL/6 mice, a mouse model of age-related hearing loss, is still unknown. Using RT-PCR, immunohistochemistry, and Western blot analysis, our results show that Bcl-2 is strongly expressed in the inner hair cells and spiral ganglion neurons of young mice. In addition, moderate Bcl-2 expression is also detected in the outer hair cells and in the neurons of the auditory cortex. A significant reduction of Bcl-2 expression in the cochlea or auditory cortex is also associated with elevated hearing thresholds and hair cell loss during aging. The expression pattern of Bcl-2 in the peripheral and central auditory systems suggests that Bcl-2 may play an important role in auditory function serving as a protective molecule against age-related hearing loss.

scholarly journals Otoferlin Is Required for Proper Synapse Maturation and for Maintenance of Inner and Outer Hair Cells in Mouse Models for DFNB9

2021 ◽  
Vol 15 ◽  
Author(s):  
Ursula Stalmann ◽  
Albert Justin Franke ◽  
Hanan Al-Moyed ◽  
Nicola Strenzke ◽  
Ellen Reisinger
Keyword(s):  
Hair Cells ◽  
Spiral Ganglion ◽  
Outer Hair Cells ◽  
Inner Hair Cell ◽  
Knock Out ◽  
Age Dependent ◽  
Synapse Maturation ◽  
Prelingual Deafness ◽  
Ganglion Neurons ◽  
Synaptic Pruning

Deficiency of otoferlin causes profound prelingual deafness in humans and animal models. Here, we closely analyzed developmental deficits and degenerative mechanisms in Otof knock-out (Otof–/–) mice over the course of 48 weeks. We found otoferlin to be required for proper synapse development in the immature rodent cochlea: In absence of otoferlin, synaptic pruning was delayed, and postsynaptic boutons appeared enlarged at 2 weeks of age. At postnatal day 14 (P14), we found on average ∼15 synapses per inner hair cell (IHC) in Otof–/– cochleae as well as in wild-type controls. Further on, the number of synapses in Otof–/– IHCs was reduced to ∼7 at 8 weeks of age and to ∼6 at 48 weeks of age. In the same period, the number of spiral ganglion neurons (SGNs) declined in Otof–/– animals. Importantly, we found an age-progressive loss of IHCs to an overall number of 75% of wildtype IHCs. The IHC loss more prominently but not exclusively affected the basal aspects of the cochlea. For outer hair cells (OHCs), we observed slightly accelerated age-dependent degeneration from base to apex. This was associated with a progressive decay in DPOAE amplitudes for high frequency stimuli, which could first be observed at the age of 24 weeks in Otof–/– mice. Our data will help to plan and predict the outcome of a gene therapy applied at various ages of DFNB9 patients.

scholarly journals Neuroplastin expression is essential for hearing and hair cell PMCA expression

2021 ◽  
Author(s):  
Xiao Lin ◽  
Michael G. K. Brunk ◽  
Pingan Yuanxiang ◽  
Andrew W. Curran ◽  
Enqi Zhang ◽  
...  
Keyword(s):  
Hair Cell ◽  
White Noise ◽  
Hair Cells ◽  
Normal Development ◽  
Single Photon ◽  
Photon Emission ◽  
Auditory Brainstem ◽  
Outer Hair Cells ◽  
Emission Computed Tomography ◽  
Cell Degeneration

AbstractHearing deficits impact on the communication with the external world and severely compromise perception of the surrounding. Deafness can be caused by particular mutations in the neuroplastin (Nptn) gene, which encodes a transmembrane recognition molecule of the immunoglobulin (Ig) superfamily and plasma membrane Calcium ATPase (PMCA) accessory subunit. This study investigates whether the complete absence of neuroplastin or the loss of neuroplastin in the adult after normal development lead to hearing impairment in mice analyzed by behavioral, electrophysiological, and in vivo imaging measurements. Auditory brainstem recordings from adult neuroplastin-deficient mice (Nptn−/−) show that these mice are deaf. With age, hair cells and spiral ganglion cells degenerate in Nptn−/− mice. Adult Nptn−/− mice fail to behaviorally respond to white noise and show reduced baseline blood flow in the auditory cortex (AC) as revealed by single-photon emission computed tomography (SPECT). In adult Nptn−/− mice, tone-evoked cortical activity was not detectable within the primary auditory field (A1) of the AC, although we observed non-persistent tone-like evoked activities in electrophysiological recordings of some young Nptn−/− mice. Conditional ablation of neuroplastin in Nptnlox/loxEmx1Cre mice reveals that behavioral responses to simple tones or white noise do not require neuroplastin expression by central glutamatergic neurons. Loss of neuroplastin from hair cells in adult NptnΔlox/loxPrCreERT mice after normal development is correlated with increased hearing thresholds and only high prepulse intensities result in effective prepulse inhibition (PPI) of the startle response. Furthermore, we show that neuroplastin is required for the expression of PMCA 2 in outer hair cells. This suggests that altered Ca2+ homeostasis underlies the observed hearing impairments and leads to hair cell degeneration. Our results underline the importance of neuroplastin for the development and the maintenance of the auditory system.

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