Human Inner Ear Immune Activity: A Super-Resolution Immunohistochemistry Study

Abstract

Background: Like the brain, the human inner ear was long thought to be devoid of immune activity. Only the endolymphatic sac (ES) was known to be endowed with white blood cells that could process antigens and serve as an immunologic defense organ for the entire inner ear. Unexpectedly, the cochlear and vestibular organs, including the eighth cranial nerve, were recently shown to contain macrophages whose functions and implication in ear disease are somewhat undefined. Here, we review recent inner ear findings in man and extend the analyses to the vestibular nerve using super-resolution structured illumination microscopy (SR-SIM). Materials and Methods: Human ESs and cochleae were collected during surgery to treat patients with vestibular schwannoma and life-threatening petro-clival meningioma compressing the brainstem. The ESs and cochleae were placed in fixative, decalcified, and rapidly frozen and cryostat sectioned. Antibodies against ionized calcium-binding adaptor molecule 1-expressing cells (IBA1 cells), laminin β2 and type IV collagen TUJ1, cytokine fractalkine (CX3CL1), toll-like receptor 4 (TLR4), CD68, CD11b, CD4, CD8, the major histocompatibility complex type II (MHCII), and the microglial marker TEME119 were used. Results: IBA1-positive cells were present in the ESs, the cochlea, central and peripheral axons of the cochlear nerve, and the vestibular nerve trunk. IBA1 cells were found in the cochlear lateral wall, spiral limbus, and spiral ganglion. Notable variants of IBA1 cells adhered to neurons with “synapse-like” specializations and cytoplasmic projections. Slender IBA1 cells occasionally protracted into the basal lamina of the Schwann cells and had intimate contact with surrounding axons. Discussion: The human eighth nerve may be under the control of a well-developed macrophage cell system. A small number of CD4+ and CD8+ cells were found in the ES and occasionally in the cochlea, mostly located in the peripheral region of Rosenthal's canal. A neuro-immunologic axis may exist in the human inner ear that could play a role in the protection of the auditory nerve. The implication of the macrophage system during disease, surgical interventions, and cell-based transplantation should be further explored.

Distribution of Immune Cells Including Macrophages in the Human Cochlea

“…Macrophages physically interacted with neighboring cells, substantiating a surveillance function. Intercellular membrane specializations were perceived between macrophages and neurons by TEM ( 11 , 60 ). Chemokines signaling may enhance target precision and molecular interaction.…”

“…Macrophages (CD163, IBA1, and CD68) are also present in the human cochlea, even in cases with no history of hearing or balance disorders ( 9 ). Super-resolution structured illumination microscopy (SR-SIM) performed in our laboratory also displayed macrophages in the human cochlea and acoustic nerve, strongly expressing the marker IBA1 (ionized calcium-binding adaptor molecule 1) and CD11b ( 10 , 11 ). The cells belong to the innate immune system but can ignite adaptive immune responses.…”

Dose-Dependent Transient Decrease of Impedances by Deep Intracochlear Injection of Triamcinolone With a Cochlear Catheter Prior to Cochlear Implantation–1 Year Data

“…Therefore, it seems unlikely that the electrode array has elicited a strong foreign body reaction. In humans, macrophages have been shown to establish direct physical contacts with both vestibular and cochlear axons and ganglion cell bodies in humans (27) and high-dose steroids suppress macrophage and progenitor cell proliferation in the brain (28). It could therefore be that a reactivation of macrophages after cessation of the application of high-dose steroids could lead to the rise of impedances to the level of the untreated controls.…”

Macrophages in the cochlea; an immunological link between risk factors and progressive hearing loss

“…The organ of Corti in the mouse has been reported not to contain macrophages (Hirose et al, 2005; Yang et al, 2015). By contrast, analysis of human temporal bones identified Iba1+ macrophages with differing morphologies in the organ of Corti (Liu et al, 2018, 2019; O'Malley et al, 2016). Super‐resolution structured illumination microscopy (SR‐SIM) and transmission electron microscopy were used in the analysis of human tissue (Liu et al, 2018, 2019), these techniques have not been reported in the mouse.…”

“…By contrast, analysis of human temporal bones identified Iba1+ macrophages with differing morphologies in the organ of Corti (Liu et al, 2018, 2019; O'Malley et al, 2016). Super‐resolution structured illumination microscopy (SR‐SIM) and transmission electron microscopy were used in the analysis of human tissue (Liu et al, 2018, 2019), these techniques have not been reported in the mouse. Macrophages in the organ of Corti are positioned along the perilymphatic side of the basilar membrane at the basal region of the tunnel of Corti and could be described as basilar membrane macrophages (Liu et al, 2018, 2019; O'Malley et al, 2016).…”