Macrophages in the Human Cochlea: Saviors or Predators—A Study Using Super-Resolution Immunohistochemistry

Abstract

The human inner ear, which is segregated by a blood/labyrinth barrier, contains resident macrophages [CD163, ionized calcium-binding adaptor molecule 1 (IBA1)-, and CD68-positive cells] within the connective tissue, neurons, and supporting cells. In the lateral wall of the cochlea, these cells frequently lie close to blood vessels as perivascular macrophages. Macrophages are also shown to be recruited from blood-borne monocytes to damaged and dying hair cells induced by noise, ototoxic drugs, aging, and diphtheria toxin-induced hair cell degeneration. Precise monitoring may be crucial to avoid self-targeting. Macrophage biology has recently shown that populations of resident tissue macrophages may be fundamentally different from circulating macrophages. We removed uniquely preserved human cochleae during surgery for treating petroclival meningioma compressing the brain stem, after ethical consent. Molecular and cellular characterization using immunofluorescence with antibodies against IBA1, TUJ1, CX3CL1, and type IV collagen, and super-resolution structured illumination microscopy (SR-SIM) were made together with transmission electron microscopy. The super-resolution microscopy disclosed remarkable phenotypic variants of IBA1 cells closely associated with the spiral ganglion cells. Monitoring cells adhered to neurons with “synapse-like” specializations and protrusions. Active macrophages migrated occasionally nearby damaged hair cells. Results suggest that the human auditory nerve is under the surveillance and possible neurotrophic stimulation of a well-developed resident macrophage system. It may be alleviated by the non-myelinated nerve soma partly explaining why, in contrary to most mammals, the human’s auditory nerve is conserved following deafferentiation. It makes cochlear implantation possible, for the advantage of the profoundly deaf. The IBA1 cells may serve additional purposes such as immune modulation, waste disposal, and nerve regeneration. Their role in future stem cell-based therapy needs further exploration.

Mitochondrial Damage and Necroptosis in Aging Cochlea

“…Significantly increased necroptosis protein, RIPK3, was significantly increased in the organ of Corti and stria vascularis. Recent studies have identified both resident macrophages (CD163-, IBA1-, and CD68-positive cells) and migrated macrophages in the human cochlea [55,56]. It is well-known that IL-1 and IL-6 are important modulators of the innate and adaptive immune responses [57].…”

Engraftment of Human Stem Cell-Derived Otic Progenitors in the Damaged Cochlea

“…43 Furthermore, active IBA-immunopositive cells were also found to be closely associated with the OHCs in the human inner ear. 44 Whether macrophages are derived from activated resident cells or represent externally recruited cells remains unknown.…”

Necroptosis and Apoptosis Contribute to Cisplatin and Aminoglycoside Ototoxicity

“…A necroptotic response in the inner ear thus would only make sense if the inner ear was not "immune privileged," as historically assumed, but was capable of mounting a significant immunological response. In fact, more recent studies suggest that the resolution of ototoxic insults is aided by immune cells infiltrating into the inner ear (Kaur et al, 2015a(Kaur et al, ,b, 2018Francis and Cunning-ham, 2017;Mizushima et al, 2017;Wood and Zuo, 2017;Barald et al, 2018;Liu et al, 2018). Such immune activity, beneficial under normal circumstances, might become counterproductive when ototoxins overwhelm the system, creating a massive, detrimental immune response.…”