Up-Regulated Expression of Interferon-Gamma, Interleukin-6 and Tumor Necrosis Factor-Alpha in the Endolymphatic Sac of Meniere's Disease Suggesting the Local Inflammatory Response Underlies the Mechanism of This Disease

Abstract

BackgroundImmune mediated inflammatory changes affecting the endolymphatic sac (ES) may underlie the pathology of Meniere's disease (MD). The aim of the present study was to explore the differentially expressed cytokines in ES luminal fluid (ELF) of patients with MD, and the correlation between the expression of cytokines in the ELF with that in the serum was determined by quantitatively analyzing the cytokines in human ELF and serum.MethodsHuman ELF, serum and ES tissues were collected from patients with unilateral MD and patients with acoustic neuroma (AN) during surgery. The Simoa Cytokine 6-Plex Panel kit was used to analyze the levels of cytokines in the ELF and blood samples of the patients. Immunohistochemistry and immunofluorescence were subsequently used to validate the relative expression levels of the cytokines in MD.ResultsSignificant differences were identified in the expression levels of interferon-γ (IFN-γ) (P < 0.001), interleukin (IL)-6 (P = 0.008) and tumor necrosis factor-α (TNF-α) (P = 0.036) in the luminal fluid of the ES comparing between the MD and AN groups. By contrast, the levels of IFN-γ, IL-10, IL-12p70, IL-17A, IL-6 and TNF-α in the serum of the MD group were not significantly different from those of either the AN group or healthy control subjects. In addition, no significant correlations in the expression levels of cytokines compared between the ELF and serum were found for the patients in either the MD or the AN group. Finally, the detection of positive expression of TNF-α, IL-6 and IFN-γ in the epithelial cells of the majority of ES specimens from patients with MD confirmed the up-regulated expression of these cytokines in the ES of patients with MD.ConclusionsThe identification of up-regulated expression levels of TNF-α, IL-6 and IFN-γ in the ELF in the present study has provided direct evidence for an increased immunologic activity in the microenvironment of the ES in patients with unilateral MD, may suggest the local inflammatory response underlies the mechanism of this disease.

Meniere's Disease Patients with Distinct Sac Pathoanatomic Findings React Differently to Endolymphatic Duct Blockage

“…Animal studies have shown that the dark cells presented in the ES of guinea pigs had a considerable secretory ability, 22 and the hyperactivity of the cells in the ES of Lewis rats could be induced by immune reactivity, leading to an increase in endolymph secretion in ES 23 . More importantly, the ES is known to be the “source” of inner ear immune response, 24 and the abnormal immune response was consistently reported in the ES of patients with MD 25–27 . As a result, when the ES was attacked by the allergic reaction, 28 viral or bacterial infection, 29 autoimmunity, 30 otitis media‐induced inflammatory products and toxins, 31 the repeated inflammatory response may have the potential to induce the hypersecretion of endolymph in these normoplastic eESs.…”

“…23 More importantly, the ES is known to be the "source" of inner ear immune response, 24 and the abnormal immune response was consistently reported in the ES of patients with MD. [25][26][27] As a result, when the ES was attacked by the allergic reaction, 28 viral or bacterial infection, 29 autoimmunity, 30 otitis media-induced inflammatory products and toxins, 31 the repeated inflammatory response may have the potential to induce the hypersecretion of endolymph in these normoplastic eESs. By contrast, the atrophic eESs determined in the present study showed a much smaller eES lumen with a vascular deficiency in its medial wall or an occluded ES lumen, suggesting the function of these eESs might be deteriorated due to their structural lesion.…”

Serum/glucocorticoid-inducible kinase 1 deficiency induces NLRP3 inflammasome activation and autoinflammation of macrophages in a murine endolymphatic hydrops model

“…Proinflammatory cytokines, such as interleukin-1β (IL-1β), have been implicated in a wide variety of middle and inner ear conditions, including MD 12 , 56 , 57 . Consistently, we found that an increasement of IL-1β both in plasma and VEO of MD patients.…”

Single cell profiling reveals a reduction of CD56dim NK-cells and other immune cells in patients with Meniere disease and high levels of cytokines

“…From the cytokines quanti ed in this study, we had observed increased levels of IL-8, TNFα, IL-4, IL-1α, MCP-1, and MIP1β in MD patients and IL-10, IL-1β, IL-6 in MDH patients. A study using endolymphatic sac luminal uid (ELF) and serum from MD patients and acoustic neuroma patients found signi cant differences in the expression of IL-6 and TNFα in ELF, but no differences were found in the serum (47). Moreover, increased levels of IL-4 and IL-10 have been found in the serum of MD patients when compared to controls (22,45).…”