c-Jun N-Terminal Phosphorylation: Biomarker for Cellular Stress Rather than Cell Death in the Injured Cochlea

Anttonen, Tommi; Herranen, Anni; Virkkala, Jussi; Kirjavainen, Anna; Elomaa, Pinja; Laos, Maarja; Liang, Xiaofang; Ylikoski, Jukka; Behrens, Axel; Pirvola, Ulla

doi:10.1523/eneuro.0047-16.2016

Cited by 18 publications

(24 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Hearing loss resulting from permanent hair cell damage or death can occur by many mechanisms, including aging, acoustic trauma, and ototoxic medications. In the setting of aminoglycoside or loop diuretic drugs, SCs in guinea pig cochlea have been demonstrated to induce heat shock proteins to attempt to protect hair cells from damage . However, if the damage is extensive and death is inevitable, SCs can activate apoptotic pathways in damaged hair cells, phagocytose dying hair cells, and expand to maintain reticular lamina integrity …”

Section: Discussionmentioning

confidence: 99%

“…In the setting of aminoglycoside or loop diuretic drugs, SCs in guinea pig cochlea have been demonstrated to induce heat shock proteins to attempt to protect hair cells from damage. 16 However, if the damage is extensive and death is inevitable, SCs can activate apoptotic pathways in damaged hair cells, phagocytose dying hair cells, and expand to maintain reticular lamina integrity. [17][18][19] Currently, the complete cascade of transcription and epigenetic factors necessary to drive transdifferentiation of adult cochlear SCs into hair cells and restore hearing remain undefined.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Supporting cell survival after cochlear implant surgery

DeTorres

Olszewski²,

López

et al. 2018

The Laryngoscope

View full text Add to dashboard Cite

Supporting cells (SCs) provide structure and maintain an environment that allows hair cells to receive and transmit signals in the auditory pathway. After insult to hair cells and ganglion cells, SCs respond by marking unsalvageable cells for death and maintain structural integrity. While the histopathology after cochlear implantation has been described regarding hair cells and neural structures, surviving SCs in the implanted ear has not. We present a patient whose posthumous examination of an implanted cochlea demonstrated SC survival. This finding has implications for SC function in maintaining electrical hearing and candidacy for future hair cell regeneration therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Supporting cell survival after cochlear implant surgery

DeTorres

Olszewski²,

López

et al. 2018

The Laryngoscope

View full text Add to dashboard Cite

show abstract

“…Since then, many diseases have been considered to have cell-autonomous etiologies and outcomes, with the assumption that pathology is caused by damage to a specific class of autonomous cells. Biologists now recognize that cells are a community, and the behavior of one cell type can influence whether another cell type lives or dies after stress (Cleveland and Rothstein, 2001 ; Barbeito et al, 2004 ; Kemp et al, 2011 ; Popiel et al, 2012 ; May et al, 2013 ; Anttonen et al, 2016 ; Halievski et al, 2016 ; Macrez et al, 2016 ; Tognatta and Miller, 2016 ; Olson et al, 2017 ). Studies of CNS diseases have provided insights into non-autonomous cell death.…”

Section: Non-autonomous Cellular Disease Pathologiesmentioning

confidence: 99%

“…Similarly, hearing loss is not simply a manifestation of autonomous HC and SGN dysfunction. Recent studies indicate that it is important to also consider the effects of ototoxic drugs on other cell types of the inner ear, including SCs and macrophages, and that these cells are critical determinants of recovery (or death) of sensory cells and neurons after ototoxic injury (Bichler et al, 1983 ; Sugawara et al, 2005 ; Ladrech et al, 2007 ; Lahne and Gale, 2008 ; Sato et al, 2010 ; May et al, 2013 ; Baker et al, 2015 ; Sun et al, 2015 ; Takada et al, 2015 ; Anttonen et al, 2016 ; Jadali and Kwan, 2016 ; Kim et al, 2016 ).…”

Section: Non-autonomous Cellular Disease Pathologiesmentioning

confidence: 99%

“… Non-autonomous cellular signals influence survival of HCs and SGNs as well as SC proliferation after ototoxic insult. (A) In response to ototoxic stress in the cochlea, SCs can promote either survival (via induction of HSP70) (Takada et al, 2015 ) or death (via activation of ERK1/2 and JNK pathways) (Lahne and Gale, 2008 ; Anttonen et al, 2016 ) of HCs. Supporting cells can also support the survival of SGNs after ototoxic injury through the release of protective neurotrophins (Sugawara et al, 2007 ; Zilberstein et al, 2012 ; Bailey and Green, 2014 ).…”

Section: Non-autonomous Cellular Responses To Ototoxic Drug-induced Hmentioning

confidence: 99%

See 1 more Smart Citation

Non-autonomous Cellular Responses to Ototoxic Drug-Induced Stress and Death

Francis

Cunningham

2017

Front. Cell. Neurosci.

View full text Add to dashboard Cite

The first major recognition of drug-induced hearing loss can be traced back more than seven decades to the development of streptomycin as an antimicrobial agent. Since then at least 130 therapeutic drugs have been recognized as having ototoxic side-effects. Two important classes of ototoxic drugs are the aminoglycoside antibiotics and the platinum-based antineoplastic agents. These drugs save the lives of millions of people worldwide, but they also cause irreparable hearing loss. In the inner ear, sensory hair cells (HCs) and spiral ganglion neurons (SGNs) are important cellular targets of these drugs, and most mechanistic studies have focused on the cell-autonomous responses of these cell types in response to ototoxic stress. Despite several decades of studies on ototoxicity, important unanswered questions remain, including the cellular and molecular mechanisms that determine whether HCs and SGNs will live or die when confronted with ototoxic challenge. Emerging evidence indicates that other cell types in the inner ear can act as mediators of survival or death of sensory cells and SGNs. For example, glia-like supporting cells (SCs) can promote survival of both HCs and SGNs. Alternatively, SCs can act to promote HC death and inhibit neural fiber expansion. Similarly, tissue resident macrophages activate either pro-survival or pro-death signaling that can influence HC survival after exposure to ototoxic agents. Together these data indicate that autonomous responses that occur within a stressed HC or SGN are not the only (and possibly not the primary) determinants of whether the stressed cell ultimately lives or dies. Instead non-cell-autonomous responses are emerging as significant determinants of HC and SGN survival vs. death in the face of ototoxic stress. The goal of this review is to summarize the current evidence on non-cell-autonomous responses to ototoxic stress and to discuss ways in which this knowledge may advance the development of therapies to reduce hearing loss caused by these drugs.

show abstract

The Stress Response in the Non-sensory Cells of the Cochlea Under Pathological Conditions—Possible Role in Mediating Noise Vulnerability

Herranen

Ikäheimo

Virkkala

et al. 2018

JARO

Self Cite

View full text Add to dashboard Cite

Various stressors, such as loud sounds and the effects of aging, impair the function and viability of the cochlear sensory cells, the hair cells. Stressors trigger pathophysiological changes in the cochlear non-sensory cells as well. We have here studied the stress response mounted in the lateral wall of the cochlea during acute noise stress and during age-related chronic stress. We have used the activation of JNK/c-Jun, ERK, and NF-κB pathways as a readout of the stress response, and the expression of the FoxO3 transcription factor as a possible additional player in cellular stress. In the aging cochlea, NF-κB transcriptional activity was strongly induced in the stria vascularis of the lateral wall. This induction was linked with the atrophy of the stria vascularis, suggesting a role for NF-κB signaling in mediating age-related strial degeneration. Acutely following noise exposure, the JNK/c-Jun, ERK, and NF-κB pathways were activated in the spiral ligament of the lateral wall of CBA/Ca mice. This activation was concomitant with the morphological transformation of macrophages, suggesting that the upregulation of stress signaling leads to macrophage activation. In contrast, C57BL/6J mice lacked these responses. Only the combination of noise exposure and a systemic stressor, lipopolysaccharide, exceeded the threshold for the activation of stress signaling in the lateral wall of C57BL/6J mice. In addition, we found that, at the young adult age, outer hair cells of CBA/Ca mice are much more vulnerable to loud sounds compared to these cells of C57BL/6J mice. These results suggest that the differential stress response in the lateral wall of the two mouse strains underlies, in part, the differential noise vulnerability of their outer hair cells. Together, we propose that the molecular stress response in the lateral wall modulates the outcome of the stressed cochlea.

show abstract

c-Jun N-Terminal Phosphorylation: Biomarker for Cellular Stress Rather than Cell Death in the Injured Cochlea

Abstract: Visual Abstract

Cited by 18 publications

References 51 publications

Supporting cell survival after cochlear implant surgery

Supporting cell survival after cochlear implant surgery

Non-autonomous Cellular Responses to Ototoxic Drug-Induced Stress and Death

The Stress Response in the Non-sensory Cells of the Cochlea Under Pathological Conditions—Possible Role in Mediating Noise Vulnerability

Contact Info

Product

Resources

About