The inner ear is an important sensor in the auditory pathway, injury to which can lead to sensorineural hearing loss. Much like the brain, it is generally believed that the inner ear is an “immune-privileged” organ because of its tight junction-based blood-labyrinth barrier. However, more recent research has confirmed that the inner ear can receive antigenic stimulation and produces an immune response. At the same time, the clinical availability of glucocorticoids and immunosuppressive agents also shows that the immune response is one of the pathophysiological mechanisms of inner ear injury. Therefore, the inflammatory response is closely related to inner ear injury, although a precise mechanism has not been determined. Understanding the specific immune response mechanism to inner ear injury will help us to treat and prevent sensorineural hearing loss more specifically.
Database search strategy
We searched the PubMed database engine until 30th March 2019 using the following keywords“aseptic inflammation”, “immune response”, “inflammatory response”, “hearing loss”, and “inner ear injury”. Only English-language published studies were included. The reference list of included studies was screened to identify other potentially useful studies. We first screened the titles and abstracts, then the full text for keywords. Not many articles that were directly relevant were identified. Therefore, we searched the database to identify relevant publications. For example, the literature search strategy for papers related to “noise-induced hearing loss” was conducted using the following keywords “noise-induced hearing loss”, “immune response”, and “inflammatory”. Papers related to infectious inflammation such as tympanitis were excluded. For each included study, we retrospectively collected and reviewed information on the authors, year of publication, study type, study sample size, and disease-related inflammatory reactions, whenever available.
Immune cells/inflammatory factors in the inner ear
Many immune cells and immune factors are involved in the inflammatory response, and most immune cells in the cochlea are macrophages. The macrophage-lymphocyte interaction was first reported in a transmission electron microscopy study of the guinea pig embryonic stem cells. In the cochlea, macrophages have been identified under normal physiological conditions. They are widely distributed, along with spiral ganglion neurons, supporting cells, and cells of the cochlear lateral wall or endolymphatic sac. Additional macrophages can enter the inner ear in response to ototoxicity or acoustic trauma. After acoustic trauma, monocytes infiltrate into the basilar membrane and the infiltrated cells are transformed into macrophages. As expected, macrophages in the inner ear perform their primary function of clearing cellular debris. However, if the inflammatory clearing action of macrophages is out of control, this causes varying degrees of nonspecific tissue damage and can lead to inflammatory and autoimmune diseases. In the inner ear, macrophages play a role in the immune response via phagocytosis of damaged cells, production of inflammatory factors, and presentation of antigens. Major histocompatibility complex class II transactivator (CIITA) is a transcriptional coactivator and controls the expression of major histocompatibility complex-II, an antigen-presenting cell molecule. The transcriptional expression of CIITA and major histocompatibility complex-II both increase in macrophages. Kaur et al found that administration of diphtheria toxin to mice caused the death of hair cells; consequently, the number of macrophages in the basilar membrane of the cochlea increased, peaking at 14 days. It has also been reported that genetic deletion of C-X3-C motif chemokine receptor 1 reduced macrophage recruitment. Altogether, this evidence suggests that macrophages play a key role in the inner ear immune response. However, some studies have found that macrophages are not the only phagocytic cells, and that supporting cells also play an important role in debris clearance.[5,6] For example, supporting cells might eliminate dying sensory hair cells to maintain epithelial integrity in the inner ear. Prestin is a protein specific to outer hair cells; however, immunolabeled cochleae after noise exposure or ototoxic injury show proteins in the Sertoli cells.
Unlike infectious inflammation, there is no related pathogen in the immune response to ototoxic drugs and noise stimulation in the cochlea. Accordingly, it is termed aseptic inflammation. Nonspecific or specific immune responses and the production of related inflammatory factors are the main immune responses in inner ear inflammatory injury. Studies have shown that activated T lymphocytes and adhesion molecules can enter the inner ear through the capillary wall of the brain, resulting in a series of immune effects. When the immune response occurs, there is an increased infiltration of T lymphocytes from the lymphatic sac of the inner ear, and these T cells and their released cytokines work in the mechanism of inner ear injury. The activation of T lymphocytes is achieved by employing specific peptides such as cochlin, which is highly expressed in the inner ear. In aseptic inflammatory regions, T cells can recognize autoantigens caused by cell fragments in the anti-injury and inflammation. They are able to recognize via their interaction with a unique T-cell receptor. As markers of inflammation, interleukin (IL)-6 and intercellular adhesion molecule 1 (ICAM-1) play a synergistic role in the process of inflammation. IL-6 is involved in a variety of immune responses, including induction of acute phase reactive protein production, induction of B cell differentiation and synthesis of antibodies, induction of killer T cells and macrophage differentiation, and induction of other cytokines. The IL6-gp130-signal transducer and activator of transcription 3 axis is necessary for the organization of the inflammatory process in animals. The complexes of IL-6 and IL-6 receptor bind to the protein gp130, induce dimerization, and initiate intracellular signaling through the Janus kinase/signal transducer and activator of transcription pathway. ICAM-1 plays an important role in leukocyte migration and stabilizing cell adhesion. The expression of IFN-γ after the secondary immune response in the endolymph capsule can up-regulate the expression of ICAM-1 and induce cell infiltration. IL-6 promotes a local inflammatory response by promoting the expression of ICAM-1. ICAM-1 can also stimulate the expression of IL-6 and promote the development of the inflammatory response via p38 or extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signaling pathways. Furthermore, Rudnicki et al proposed that pentraxin 3 is a key regulator of the immune response, a component of the humoral arm of innate immunity in inner ear inflammation. The authors proposed a miR-224-Ptx3 regulatory axis, which is a miRNA regulatory pathway activated in response to inflammation in the inner ear. Both miR-224 and Ptx3 are expressed in hair and supporting cells. In the inner ear immune response, nuclear factor kappa B (NF-κB), a key transcription factor in the immune response, is activated by tumor necrosis factor-α and IL-1β, and subsequently up-regulates the expression of miR-224. miR-224, along with NF-κB transcriptional regulation, is part of the inflammation pathway in the inner ear. Ptx3 is a target of miR-224 and both are mediators of inflammation. miR-224 reduces the innate immune response by down-regulating Ptx3 expression, whereas the Ptx3 stimulates the innate immune response and is directly involved in the inflammatory response and recruitment of the complement system. At the same time, miR-224 and Ptx3 form a feedback loop to protect the inner ear from inflammation-induced injury. A previous study found that miR-224 also targets Smad4 directly. Smad4 plays an important role in the development process of the inner ear. Specific Smad4 knockout mice have been reported to show abnormal vestibular organ structure and hair cell development in the cochlear. Smad4 is a major mediator of the transforming growth factor (TGF)-β anti-inflammatory signaling pathway. miR-224 may be involved in the anti-inflammatory pathway of the inner ear by down-regulating Smad4. Therefore, regulating the function of cochlear inflammatory cells or factors may be an effective method for the prevention and treatment of inner ear injury.
The pathophysiological mechanisms of inner ear diseases in immunity/inflammation
At present, the mechanism underlying immune and inflammatory-mediated inner ear diseases has not been fully clarified. According to one review, the main mechanisms underlying the immune response in tissues and organs are the presence of autoantibodies against tissue antigens, followed by the deposition of antigen-antibody complexes in tissues. Finally, cytotoxic T cells enter and destroy the tissue. However, few reports have investigated these mechanisms in the inner ear of humans. Elucidating the immune mechanism of common diseases associated with inner ear injury could help us to identify therapeutic targets, such as immune/inflammatory factors and immune cells (especially macrophage cells), to regulate the inner ear immune system and improve hearing.
Sudden sensorineural hearing loss
Sudden sensorineural hearing loss (SSNHL) is a multifactorial disease, and previous studies have shown that inflammation may be associated with its pathogenesis. One study reported a correlation between IL-6 and ICAM-1 levels with the incidence of sudden deafness. An increase in plasma levels of IL-6 and ICAM-1 may increase the risk of sudden deafness. For example, Tian et al performed a case-controlled study with 75 patients with SSNHL and 125 controls, and found that the combination of IL-6 and ICAM-1 has a synergistic effect on the onset of SSNHL. At the same time, gene polymorphism affects gene transcription and translation, and then affects IL-6 and ICAM-1 expression in plasma. The combination of the G allele in IL-6 and E allele in ICAM-1, namely, CG/GG and KE/EE genotypes, showed a higher prevalence in patients than in controls. Another study reported that a decrease of natural killer cell activity (NKCA), an increase of acute neutrophil count, and an increase of IL-6 can induce NF-κB activation in the inner ear and cause severe SSNHL. Ulu et al measured the neutrophil-to-lymphocyte ratio in 47 patients with SSNHL and 45 healthy subjects. The neutrophil-to-lymphocyte ratio values in patients with SSNHL were significantly higher than those of healthy controls. These findings indicate that decreased NKCA can lead to systemic immune system disorders, resulting in an increase in neutrophils. Notably, NKCA is reduced by fatigue, daily stress, and short sleeping durations, which are also thought to be the cause of sudden sensorineural hearing loss. In another way, IL-6 has been found to induce neutrophilia. All of this leads to an increase in the number of neutrophils in the cochlea of patients. Elevated neutrophils can induce abnormal NF-κB activation in the cochlear lateral wall via the NF-κB stress response system, and then activate a stress response in the cochlear lateral wall. In another study, Yoon et al found that interferon-γ levels in patients with SSNHL were obviously lower than those in control subjects. This may be related to the involvement of interferon-γ in the immune response to injury of the inner ear and its large amounts of consumption. At the protein level, Garcia et al analyzed the presence of circulating immune complexes and heat shock protein 70 (HSP70) using a simple dot blot method, and found elevated levels of immune complexes in 59.4% of patients with SSNHL. At the same time, the presence of free HSP70 protein in serum was found in 48.4% of patients. HSP70 is an intracellular cryptic protein, and, as an antigen, it may stimulate immunological mechanisms. Together, these results suggest that the immune/inflammatory response is an important mechanism that mediates sudden deafness.
Noise-induced hearing loss
Noise overexposure can injure hair cells, which leads to auditory dysfunction. Acoustic damage activates the immune system in the cochlea, which results in the generation of inflammatory mediators and the infiltration of immune cells. However, the molecular mechanism responsible for initiating these immune responses is still unclear. A recent study investigated the functional effects of Toll-like receptor 4 (TLR-4). They found that the expression of TLR-4 in rat cochlear sensory cells increased after noise stimulation. Further immunohistochemical detection showed that the expression of TLR-4 was concentrated in Sertoli cells that were surrounded by dead hair cells. TLR-4 recruits adaptor molecules and activates different aspects of the inflammatory immune response. On the one hand, the lack of function of TLR-4 inhibits the production of the pro-inflammatory molecule IL-6 after acoustic injury. However, TLR-4 knockout inhibits the expression of major histochemical compatibility complex II, which are antigen presenting molecules in macrophages. This indicates that TLR-4 participates in the antigen presenting function of macrophages after auditory injury.[19,20] Furthermore, the TLR-4 signaling pathway is an upstream regulator of the cochlear immune response, and acoustic overstimulation has been found to cause an upregulation of the TLR-4 gene. After transcriptome sequencing of the sensory epithelium in the cochlea of mice exposed to noise, one study found that the expression of immune factors gene which are downstream factors of TLR-4 signaling pathway was up-regulated. Some studies have demonstrated that the noise-overstimulated cochlea increases the production of pro-inflammatory cytokines, including IL-6, IL-1β, and tumor necrosis factor-α,[22,23] IL-6 is a factor that is expressed in the stria vascularis, spiral ligament, and spiral ganglion neurons. Wakabayashi et al found that blocking IL-6 signaling suppressed the cochlear inflammatory response. It is possible that the release of tumor necrosis factor-α and IL-1β after noise overexposure activates the NF-κB signaling pathway and results in the expression of other pro-inflammatory mediators, such as cell adhesion molecules, cytokines, and chemokines.[25,26] Murillo-Cuesta et al studied the auditory function and cochlear morphology of noise overexposed mice treated with TGF-β peptide inhibitors; their results indicated that TGF-β1 inhibition protected the cochlear from hearing loss. The TGF-β family is the key regulator of immune and inflammatory responses; however, the role of TGF-β has not yet been determined. In this work, it was found that gene expression of TGF-β1 and the TGF-β1 receptor increased in the 24 hours immediately after noise exposure. These high levels of TGF-β1 continued for 48 hours and returned to normal after 7 days. This suggests that TGF-β1 plays a role in the initial stage of inflammation. In the early stage of tissue injury, TGF-β1 regulates the expression of adhesion molecules and induces the chemical attraction and activation of white blood cells. The overexpression of TGF-β1 in the inner ear is also related to fibrosis of the cochlea. Together, these findings indicate that one response of the cochlea to noise stimulation is an immune inflammatory response. Furthermore, regulation of the immune inflammatory response could have therapeutic implications for noise-induced deafness.
Age-related hearing loss
Age-related hearing loss is the most common sensory disorder in elderly individuals, and is a progressive loss of hearing sensitivity due to the degeneration of sensory or transduction neurons in the peripheral and central auditory systems. An increased production of reactive oxygen and inflammatory response have been found in aging cochleae.[28,29] The chronic inflammatory response is an important contributor to many kinds of age-related pathologies, and can also be seen in the inner ear. However, few studies have investigated the potential function of the immune response in age-related hearing loss. One cross-sectional survey found that serum C-reactive protein and IL-6 were significantly higher in people under 60 years old with hearing loss than those with normal hearing. In a recent study, Shi et al found significantly increased levels of activated caspase-1, IL-1β, IL-18, NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) in the inner ears of aging mice; the mechanism of the increase of these factors is related to the inflammatory response induced by oxidative stress. Oxidative stress has been implicated as playing a major role in the pathophysiology of age-related hearing loss. The excessive accumulation of ROS is toxic to cells and can cause apoptosis in the inner ear. Moreover, ROS accumulation can interact with other pathological activities, such as the inflammatory response. NLRP3, as a sensor protein of ROS, may contribute to inflammasome assembly and subsequent inflammation in the cochleae. The expression of both NLRP3 mRNA and protein has been reported to be markedly increased in aging mouse cochleae. NLRP3 recruits Asc and allows Asc to bind with caspase-1. Caspase-1 is then activated in the inflammasome assembly, which promotes the maturation of downstream inflammatory cytokines IL-1β and IL-18. In another study, Riva et al studied the auditory function of CD/1 mice (the outbred CD/1 mouse strain commonly shows accelerated presbycusis) at 4, 12, and 24 weeks of age, and found that the expression of tumor necrosis factor-α increased with increasing age. This could be because subsequent disturbances of cellular signaling cascades caused by ROS ultimately lead to apoptosis (detected by activated caspase-3) accompanied with inflammation (in the presence of tumor necrosis factor-α). Tumor necrosis factor-α is a strong promoter of inflammation and cell death.
Macrophages are important cells that are involved in the immune response of the inner ear; thus, the down-regulation of macrophage migration inhibitory factor (MIF) could aggravate the development of age-related deafness. MIF is a multi-functional factor. Kariya et al used MIF-deficient mice (MIF-/- mice) to identify the role of MIF. They first examined the expression of MIF in the inner ear of WT and positive immunostaining for MIF was observed in the spiral ligament, stria vascularis, and organ of Corti. Older MIF-/- mice showed accelerated age-related hearing loss and inner ear abnormalities. This demonstrates that macrophages play a role in the development of age-related hearing loss, and that MIF could prevent this process. Together, this evidence indicates that inflammation/the immune response is an important mechanism for the development of age-related hearing loss.
Meniere's disease (MD) is a rare disease that affects the inner ear, and is characterized by vertigo lasting from 20 minutes to hours, tinnitus, sensorineural hearing loss, and aural fullness. It is well-known that some patients with Meniere's disease have significant recovery of SNHL or vertigo after systemic corticosteroid treatment; therefore, the immune-mediated mechanism is related to the pathology of MD. Many studies have found evidence of a contribution of autoimmunity in the pathogenesis of MD, and the main pathological mechanism of MD is hydrocele of the membranous labyrinthine of the cochlea. The endolymphatic sac is an immunocompetent organ of the inner ear. Thus, one hypothesis is that the inflammatory response occurs in the endolymphatic sac; indeed, some studies have reported that there are many immunoglobulins in the endolymphatic sac. For example, Kim et al performed one-dimensional electrophoresis and liquid column mass spectrometry to measure the protein composition of the endolymph of patients with MD. They found that 76% of detected proteins were immunoglobulin and its variants, such as albumin, keratin, transferrin, and protease inhibitor. This is indicative of inflammatory or immune reactions in the endolymphatic sac. The sac has a crucial role, not only in the maintenance of endolymph composition, but also in the innate immune response. After exposure to environmental trigger factors, there may be an abnormal NF-κB mediated inflammatory response in the endolymph sac, which leads to ion imbalance in the endolymph and accumulation of endolymph in the cochlear duct. A second hypothesis is that there is an increase of NF-κB in the spiral ligament and spiral edge fibroblasts after the release of pro-inflammatory cytokines. Frejo et al studied the regulation of the Fn14 receptor, and found that NF-κB underlies inflammation in MD. NF-κB is a family of transcription factors that regulate immune and inflammatory responses. The tumor necrosis factor-related weak inducer of apoptosis/Fn14 pathway activates NF-κB, probably increasing the inflammatory response in MD. Therefore, the Fn14 receptor and NF-κB could be potential targets for MD drug therapy. A third hypothesis is that Meniere's disease is associated with autoimmune diseases. MD has been associated with an elevated prevalence of systemic autoimmune disease, such as systemic lupus erythematosus, rheumatoid arthritis, and ankylosing spondylitis. This suggests that the pathophysiology of MD is associated with autoimmunity, much like other autoimmune disease. The TWEAK/Fn14 pathway is involved in inflammatory regulation of several chronic autoimmune disease; however, this pathway has not yet been studied in the context of SNHL or MD. Furthermore, 1 study reported higher levels of autoantibodies, circulating immune complexes, and antigen-antibody reactions in the serum of patients with MD. Previous studies have also shown that an immune response driven by circulating immune complexes induced inner ear damage. Lopez-Escamez et al used polymerase chain reaction-based TaqMan genotyping assay to analyze CD16A and CD32A single nucleotide polymorphisms. The authors found elevated circulating immune complexes in 7% of patients with MD during the intercrisis period. Some studies have also reported the presence of antibodies against internal ear antigens, such as antibodies to the HSP70 antigen and antibodies to myelin protein zero protein. Based on the above findings, if autoimmunity is one of the causes of Meniere's disease, then detecting autoantibodies or inflammatory materials could be useful.
Autoimmune inner ear disease
Autoimmune inner ear disease (AIED) is a rare disease that is often caused by an ‘uncontrolled’ immune system response, and occurs as a part of a systemic autoimmune disease. Steroid and immunosuppressive therapy is effective and it has been reported that hearing improved or stabilized after treatment with an IL-1 blocker. Thus, it is believed that an immune response is involved in AIED. Several possible underlying mechanisms of AIED have been suggested, as follows: 1) deposition of circulating immune complexes (responsible for type III immune response): The deposition of immune complexes in vascular stripes have been found in C3H/lpr autoimmune mice with progressive hearing loss, and the deposition of IgM and IgG immune complexes have been found in NZB/kl mice with high hearing loss; 2) Vestibule-cochlear autoantibodies: In 1 study, the antibodies in the inner ear of patients with SSHL were analyzed using Western blotting. It was found that there were IgG antibodies against the inner ear-specific proteins cochlin and β-tectorin and the nonspecific protein HSP-70. In 1 study cohort, researchers compared the antibody reactivity of the recombinant cochlin and HSP70 antigens in patients with idiopathic sensorineural hearing loss. In the same study cohort, they also used a western blot assay to assess IgG antibody responses to the recombinant human HSP70. Of the 58 patient samples analyzed, 19 tested positive for the HSP70; thus, HSP70 may be a marker of AIED. However, Yeom et al found that HSPs are not appropriate substrates for serodiagnosis of autoimmune sensorineural hearing loss by testing the antibody reactivity against multiple HSP 70 substrates from 20 patients with progressive sensorineural HL and 20 control volunteers; 3) T cell-mediated autoreactivity to the inner ear membrane: A misdirected attack leads to proinflammatory T cell responses and autoantibody formation. Baek et al found that patients with AIED have higher frequencies of circulating T cells compared with normal hearing individuals. They also found that CD4+ and CD8+ T cells are involved in cochlin recognition, and that patients with AIED have elevated cochlin antibody titers. Billings also immunized SWXJ mice with cochlin 131–150 and confirmed that CD45+ T cells infiltrate the cochlea and cause autoimmune SSHL. Together, this evidence indicates that autoimmune hearing loss can be caused by cytotoxic T cell-mediated organ-specific autoimmune disorders of the inner ear.
In the past few decades, there has been an increasing interest in the field of ear science and more experimental evidence for the presence of inflammatory and immune responses in the inner ear. Although we have observed some immune cells and inflammatory factors in the inner ear using experimental techniques such as epidemiological surveys and analysis, immunological tests, and models of experimental labyrinthitis by autoantibodies, the specific mechanisms and their interactions remain unclear. To summarize, the inner ear can no longer be considered as an “immune-privileged” organ, and immune and inflammatory reactions play an essential role in the pathogenesis of inner ear disease. Access to the inner ear is limited and there are no specific markers for autoimmune inner ear disease; these issues represent challenges that have yet to be overcome. Many mechanistic questions remain and much research remains to be conducted; however, the establishment of new bio-analysis technologies and experimental animal models will help to uncover the mysteries of inflammatory mechanisms in the inner ear injury. It is believed that the future of the inner ear immunology and inner ear disease treatment is bright.
YW contributed to acquisition and analysis of data and manuscript writing. DR reviewed the literature and contributed to conception and design of the work and critical revision of the manuscript for important intellectual content. All authors approved the final manuscript.
This work was supported by National Key R&D Program of China (Nos. 2016YFC0905200, 2016YFC0905202); the National Natural Science Foundation of China (Nos. 81420108010, 81771017, 81570920).
Conflicts of interest
The authors declare that they have no conflict of interest.
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