Role of Inner Ear Macrophages and Autoimmune/Autoinflammatory Mechanisms in the Pathophysiology of Inner Ear Disease

Miwa, Toru; Okano, Takayuki

doi:10.3389/fneur.2022.861992

Cited by 13 publications

(7 citation statements)

References 99 publications

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“…This deposition caused damage to the capillary endothelium, leading to increased vascular permeability, ultimately resulting in endolymphatic hydrops and disruption of the outer hair cells. This proposed mechanism finds support in histopathologic observations from temporal bone studies in both humans and animals [12]. Another study demonstrated that AIED often involves dysfunctional immune responses in peripheral blood mononuclear cells to cochlear antigens.…”

Section: Pathophysiology Of Inner Ear Diseases In Autoimmune and Auto...mentioning

confidence: 71%

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Decoding the impact of autoinflammatory/autoimmune diseases on inner ear harmony and hearing loss

Athanasopoulos,

Samara,

Athanasopoulos

2024

Explor Immunol

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Autoimmune and autoinflammatory diseases affecting the inner ear can cause symptoms such as hearing loss, imbalance, vertigo, and tinnitus, presenting demanding and often underdiagnosed conditions. Diagnostic challenges arise due to their diverse manifestations, potential long-term consequences, and the absence of specific serological markers, necessitating a multidisciplinary approach combining clinical evaluation, audiological assessments, and imaging techniques. Various autoimmune disorders, including systemic lupus erythematosus, rheumatoid arthritis, and Sjogren’s syndrome, have been implicated in immune-mediated damage to auditory structures, resulting in inner ear dysfunction. Inflammatory processes in autoinflammatory diseases like Cogan’s syndrome and relapsing polychondritis can also affect the inner ear. While the exact mechanisms of inner ear involvement in these conditions are still being studied, immune-mediated inflammation, damage to auditory structures, and vascular involvement play significant roles in auditory impairments. Treatment strategies primarily focus on immunomodulation and inflammation control using corticosteroids, immunosuppressants, and targeted biologic agents to ameliorate symptoms and preserve hearing function. Hearing aids and cochlear implants may be also considered for severe hearing loss. Individualized approaches are necessary due to patient response heterogeneity. This review provides a concise overview of key autoimmune and autoinflammatory diseases impacting the inner ear, highlighting clinical manifestations, diagnostics, pathophysiology, and treatment options. Early recognition and appropriate management are crucial for optimizing patient outcomes. Further research is needed to understand underlying mechanisms and identify novel therapeutic targets. Collaboration between otolaryngologists, rheumatologists, and immunologists is crucial for improving the quality of life in these complex conditions.

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Section: Pathophysiology Of Inner Ear Diseases In Autoimmune and Auto...mentioning

confidence: 71%

“…Autoimmune and autoinflammatory diseases can affect the inner ear through various mechanisms, although the precise details for all conditions are not fully determined. Presented below are some of the primary mechanisms involved [12]:…”

Section: Pathophysiology Of Inner Ear Diseases In Autoimmune and Auto...mentioning

confidence: 99%

Decoding the impact of autoinflammatory/autoimmune diseases on inner ear harmony and hearing loss

Athanasopoulos,

Samara,

Athanasopoulos

2024

Explor Immunol

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“…The fractalkine signaling pathway has been researched on its participation in the circulation and recruitment of cochlear macrophages: Cx3cr1 (the receptor for fractalkine)‐positive macrophages are recruited into the spiral ganglion for the survival of spiral ganglion neurons, subsequent to HC death induced by diphtheria toxin (Kaur et al, 2015); on the other hand, Cx3cr1‐positive macrophages migrate into the greater epithelial ridge (GER) in response to apoptosis of GERCs, a required process for the inner sulcus formation during cochlear maturation, but the fractalkine signaling pathway is not indispensable for this maturation process (Borse et al, 2021). These cochlear macrophages are presumably maintained not only by self‐renewal through proliferation but also by supply from HSCs after birth, especially in adulthood, as demonstrated by the bone marrow transplantation system as with other types of tissue‐resident macrophages (Miwa & Okano, 2022; Okano et al, 2008). Notably, these cochlea‐resident macrophages were reported not to be found within the organ of Corti (Hirose et al, 2005; Hough et al, 2022; Okano et al, 2008).…”

Section: Cochlear Scs Are Enabled To Acquire Macrophage Phenotypes Du...mentioning

confidence: 99%

Signaling pathways regulating the immune function of cochlear supporting cells and their involvement in cochlear pathophysiology

Hayashi

2023

Glia

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The inner ear, including the cochlea, used to be regarded as an immune‐privileged site because of its immunologically isolated environment caused by the blood‐labyrinthine barrier. Cochlear resident macrophages, which originate from the yolk sac or fetal liver during the embryonic stage and are maintained after birth, are distributed throughout various regions of the cochlear duct. Intriguingly, these cells are absent in the organ of Corti, where hair cells (HCs) and supporting cells (SCs) are located, except for a limited number of ionized calcium‐binding adapter molecule 1 (Iba1)‐positive cells. Instead, SCs exert glial functions varying from a quiescent to an emergency state. Notably, SCs acquire the nature of macrophages and begin to secrete inflammatory cytokines during viral infection in the organ of Corti, which is ostensibly unprotected owing to the lack of general resident macrophages. This review provides an overview of both positive and negative functions of SCs enabled to acquire macrophage phenotypes upon viral infection focusing on the signaling pathways that regulate these functions. The former function protects HCs from viral infection by inducting type I interferons, and the latter function induces HC death by necroptosis, leading to sensorineural hearing loss. Thus, SCs play contradictory roles as immune cells with acquired macrophage phenotypes; thereby, they are favorable and unfavorable to HCs, which play a pivotal role in hearing function.

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“…BLB disruption secondary to cochlear immune and in ammatory responses is a potential contributor to the pathogenesis of hearing loss, and have been associated not only with middle and inner ear infections, but also with autoimmune disorders, acoustic trauma, ototoxicity, presbycusis, and Meniere's disease, among others (11,(25)(26)(27)(28). Preventing inner ear in ammation is thus a clinical aspiration (29).…”

Section: Introductionmentioning

confidence: 99%

Protection of lipopolysaccharide-induced otic injury by a single dose administration of a novel dexamethasone formulation

Murillo-Cuesta,

Lara,

Bermúdez-Muñoz

et al. 2023

Preprint

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Background. The blood-labyrinth barrier (BLB) separates the inner ear from the circulation and is critical for maintaining ionic homeostasis and limiting the entry of deleterious agents. BLB integrity is disrupted by bacterial lipopolysaccharide (LPS), among other deleterious agents, which elicits a strong inflammatory response in the inner ear leading to irreversible otic damage. Prolonged administration of systemic corticosteroids is the available treatment, which shows both limited efficacy and major adverse effects. SPT-2101 is a novel in situ-forming gel formulation of dexamethasone allowing slow and sustained drug release after single intratympanic administration. Methods. We used a rat model of LPS-induced injury to define the functional, cellular and molecular mechanisms associated to BLB dysfunction and the protection by SPT-2101. Hearing was assessed by auditory brainstem response (ABR) recording, BLB permeability by gadolinium dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and Evans blue extravasation. Gross cochlear histology and cellular alterations were studied by hematoxylin-eosin staining and immunofluorescence. RT-qPCR, PCR array and western blotting were used to assess transcriptional and protein changes. Results. LPS-challenged rats showed BLB breakdown and altered permeability as shown by the progressive increase in cochlear gadolinium uptake and Evans blue incorporation. LPS administration increased the cochlear expression of the LPS toll-like receptors Tlr2 and co-receptor Cd14, pro-inflammatory cytokines and receptors such as Il1b and ll1lr, and also the oxidative stress and inflammasome mediators NRF2 and NLRP3. LPS also increased IBA1-positive macrophage infiltration in the lateral wall and spiral ganglion. A single intratympanic injection of SPT-2101 protected BLB integrity and prevented otic injury. Comparable effects were obtained by repeated administration of systemic dexamethasone, but not by a single dose. SPT-2101 administration normalized molecular inflammatory mediators and suppressed macrophage infiltration. Conclusions. Our data indicate that single local administration of dexamethasone formulated as SPT-2101 protects BLB functional integrity during endotoxemia, providing a novel therapeutic opportunity to treat diseases related to BLB dysfunction.

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Role of Inner Ear Macrophages and Autoimmune/Autoinflammatory Mechanisms in the Pathophysiology of Inner Ear Disease

Cited by 13 publications

References 99 publications

Decoding the impact of autoinflammatory/autoimmune diseases on inner ear harmony and hearing loss

Decoding the impact of autoinflammatory/autoimmune diseases on inner ear harmony and hearing loss

Signaling pathways regulating the immune function of cochlear supporting cells and their involvement in cochlear pathophysiology

Protection of lipopolysaccharide-induced otic injury by a single dose administration of a novel dexamethasone formulation

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