NLRP3 inflammasome activation in human vestibular schwannoma: Implications for tumor-induced hearing loss

Sagers, Jessica E.; Şahin, Mehmet İlhan; Moon, In Seok; Ahmed, SG; Stemmer‐Rachamimov, Anat; Brenner, Gary J.; Stanković, Konstantina M.

doi:10.1016/j.heares.2019.07.007

Cited by 37 publications

(52 citation statements)

References 31 publications

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“…It is also possible that an immune mediated mechanism could play a role in the pathophysiology of hearing loss progression, as immune and inflammatory mechanisms have previously been found to occur in other inner ear pathologies such as Ménière's disease, DFNA34 hearing loss and related autoimmune and autoinflammatory diseases of the inner ear ( 24 – 26 ). A growing field of evidence suggests that inflammation is a key feature of the VS microenvironment as well, such as excessive activation of the NLRP3 inflammasome leading to upregulation of associated proteins NLRP3 and IL-1β, which have been preferentially upregulated in tumors associated with increased hearing loss ( 12 , 27 ). The relative impact on thresholds vs. word understanding in contralateral ears can provide clues to the nature of which VS-secreted factors or immune mediated responses may be responsible for causing hearing loss in the VS-ipsilateral ear, and can guide further research in this direction.…”

Section: Discussionmentioning

confidence: 99%

“…The greater the severity of SNHL associated with a VS tumor, the greater the degree of hair cell loss and neuronal fiber disorganization seen in cochlear explants exposed to tumor secretions (11,13). In addition, the degree of SNHL tends to be greater in patients whose tumors overexpress the NLRP3 inflammasome and the associated ototoxic molecules such as IL1β (12). These findings suggest secreted mechanisms for SNHL in patients with VS, independent of mechanical compression of the cochlear nerve.…”

Section: Introductionmentioning

confidence: 87%

“…These clinical observations suggest additional explanations for the pathophysiology of SNHL, beyond only mechanical compression of adjacent structures. Recent studies have revealed new insights about the capacity of secreted factors, such as tumor necrosis factor alpha (TNFα), and extracellular vesicles (EVs) from human VSs to cause cochlear damage (11)(12)(13)(14)(15)(16). The greater the severity of SNHL associated with a VS tumor, the greater the degree of hair cell loss and neuronal fiber disorganization seen in cochlear explants exposed to tumor secretions (11,13).…”

Section: Introductionmentioning

confidence: 99%

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Progression of Contralateral Hearing Loss in Patients With Sporadic Vestibular Schwannoma

et al. 2020

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Background and Introduction: Vestibular schwannomas (VSs) are the most common tumors of the cerebellopontine angle, typically presenting unilaterally with ipsilateral sensorineural hearing loss (SNHL). The mechanism of tumor-induced hearing loss has recently been shown to be related to secreted tumor factors, in addition to mechanical compression of the adjacent auditory nerve, and these factors may percolate through CSF or blood to affect contralateral hearing as well. Methods: This is a retrospective study of medical records for patients treated for VS at Mass Eye and Ear from January 1994 through October 2018. Included patients had unilateral VS and sequential audiometry allowing for longitudinal assessment of hearing over time. Mass Eye and Ear's audiology database was used to select age-and sex-matched case controls, also with sequential audiometry, from the non-VS population. Subgroup analysis was performed by age, sex, baseline hearing, and tumor size at initial diagnosis. Hearing loss progression was performed using Kaplan-Meier analysis to account for variable follow-up times. Results: A total of 661 patients were identified with VS and sequential audiometry. The population was predominantly female vs. male (368 vs. 293, p = 0.0035), driven primarily by younger patients with Koos 4 tumors (76 female vs. 49 male, p = 0.016). Patients with normal baseline hearing bilaterally (N = 241) demonstrated no significant difference in hearing loss progression in VS-contralateral vs. control ears. Patients with abnormal baseline VS-ipsilateral hearing (N = 190), however, demonstrated significantly higher likelihood of reaching moderate SNHL in VS-contralateral ears. Subgroup analysis by age, sex, and baseline tumor size did not yield any subgroup-specific trends for hearing loss progression. Discussion and Conclusion: This is the largest study to date tracking long-term bilateral hearing outcomes in patients with VS, and demonstrates that, in patients with abnormal hearing in the VS-ipsilateral ear, there exists a long-term risk of progression to moderate hearing loss in the contralateral ear as well. Combined with the absence Early et al. Vestibular Schwannoma Contralateral Hearing Loss of significant changes in word understanding in the affected ears, these findings may provide clues to the nature of tumor-secreted factors involved in VS-associated hearing loss. Female predominance within the VS patient population is confirmed, driven mostly by younger female patients with Koos 4 tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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Progression of Contralateral Hearing Loss in Patients With Sporadic Vestibular Schwannoma

et al. 2020

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“…The pathophysiology of ICS leading to abnormal VEMPs is unknown and can only be speculated about. In patients with cochleovestibular schwannomas (without intracochlear localization of tumors), it has been reported that sensorineural hearing loss is associated with tumorsecreted factors containing pro-inflammatory cytokines which cause cochlear damage (59,60). This could explain why large cochleovestibular schwannomas sometimes do not cause hearing loss while small ones do.…”

Section: Discussionmentioning

confidence: 99%

“…It should be examined, how the VEMP amplitudes and latencies change over time, possibly in the course of tumor growth. Regarding the different outcomes, i.e., especially reduced or absent in contrast to normal or enhanced VEMPs, the tumors' intrinsic biology with respect to tumor secreted factors should be investigated as was done for cochleovestibular schwannomas causing hearing loss (59,60). This is important to assess the clinical relevance of normal, absent or reduced, and enhanced VEMPs and might become beneficial for counseling ICS patients.…”

Section: Discussionmentioning

confidence: 99%

Cervical and Ocular Vestibular-Evoked Myogenic Potentials in Patients With Intracochlear Schwannomas

et al. 2020

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Objective: To evaluate ocular and cervical vestibular evoked myogenic potentials (oVEMPs and cVEMPs) in patients with solely intracochlear localization of an intralabyrinthine schwannoma (ILS).Study Design: Retrospective analysis of a series of cases.Setting: Monocentric study at a tertiary referral center.Patients: Patients with intracochlear schwannoma (ICS) and VEMP measurements.Outcome Measures: Signed asymmetry ratio (AR) of cVEMPs and oVEMPs to air conducted sound with AR cut-offs considered to be asymmetrical when exceeding ±30% for cVEMPs and ±40% for oVEMPs with respect to the side affected by the tumor (reduced amplitudes on the affected side indicated by negative values, enhanced amplitudes by positive values); VEMP amplitudes and latencies; tumor localization in the cochlear turn and scala.Results: Nineteen patients with a solely intracochlear tumor (ICS patients) [10 males, 9 females, mean age 57.1 (SD: 13.4) years] were included in the study. On the affected side, cVEMPs were absent or reduced in 47% of the patients, normal in 32%, and enhanced in 21%. Ocular VEMPs on the affected side were absent or reduced in 53% of the patients, normal in 32% and enhanced in 15%. Latencies for cVEMPs and oVEMPs were not significantly different between the affected and non-affected side. In all patients with enhanced VEMPs, the tumor was located in the scala tympani and scala vestibuli. Conclusions:As a new and unexpected finding, VEMP amplitudes can be enhanced in patients with intracochlear schwannoma, mimicking the third window syndrome.

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Immune Profiling of Secreted Factors from Human Vestibular Schwannoma Cells and Tumor‐associated Macrophages

Stankovic,

Batts,

Welling

et al. 2023

The Laryngoscope

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ObjectivesThis study compared the immune‐related secretory capacity of human vestibular schwannoma (VS) and tumor‐assisted macrophages (TAMs) with their normal counterparts (Schwann cells [SC] and peripheral blood monocyte‐derived macrophages [Mo‐MFs], respectively), and examined relationships with presurgical hearing and tumor size.MethodsVS tumors (n = 16), auditory nerve (n = 1), blood (n = 9), and great auricular nerves (n = 3) were used. SCs (S100B+) and TAMs (CD68+) were isolated from VS tissue for culture. The secreted levels of 65 immune‐related factors were measured and compared using unpaired t‐tests with Welch correction (schwannoma vs. SCs) or Mann–Whitney tests (TAMs and Mo‐MFs). Associations between factor concentration and word recognition (WR), pure‐tone average (PTA), and tumor size were evaluated with Spearman correlation.ResultsSecreted factors with significantly higher concentrations in schwannoma versus SC supernatants included IL‐2 and BAFF, whereas MMP‐1, IL‐6, FGF‐2, VEGF‐A, MIP‐3α, and GRO‐α concentrations were significantly higher in TAMs versus Mo‐MFs (all p < 0.05). Worse WR was significantly associated with higher secretion of fractalkine, eotaxin‐3, CD30, and IL‐16 by VS cells; IP‐10, eotaxin‐3, multiple interleukins, GM‐CSF, SCF, and CD30 by TAMs; and TNF‐α and MIP‐1α by Mo‐MFs (all p < 0.05). Worse PTA was significantly correlated with higher secretion of IL‐16 by VS cells (p < 0.05). Larger tumor size was significantly correlated with higher secretion of eotaxin by VS cells, and of IL‐7, IL‐21, and LIF by TAMs (all p = 0.017).ConclusionsDifferential secretion of immune‐related factors was observed in schwannoma versus normal SCs and in TAMs versus Mo‐MFs, some of which were correlated with worse hearing and larger VS tumors.Level of EvidenceN/A Laryngoscope, 2023

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NLRP3 inflammasome activation in human vestibular schwannoma: Implications for tumor-induced hearing loss

Cited by 37 publications

References 31 publications

Progression of Contralateral Hearing Loss in Patients With Sporadic Vestibular Schwannoma

Progression of Contralateral Hearing Loss in Patients With Sporadic Vestibular Schwannoma

Cervical and Ocular Vestibular-Evoked Myogenic Potentials in Patients With Intracochlear Schwannomas

Immune Profiling of Secreted Factors from Human Vestibular Schwannoma Cells and Tumor‐associated Macrophages

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