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

Abstract

Macrophages are abundant in the cochlea; however, their role in hearing loss is not well understood. Insults to the cochlea, such as noise or insertion of a cochlear implant, cause an inflammatory response, which includes activation of tissue‐resident macrophages. Activation is characterized by changes in macrophage morphology, mediator expression, and distribution. Evidence from other organs shows activated macrophages can become primed, whereby subsequent insults cause an elevated inflammatory response. Primed macrophages in brain pathologies respond to circulating inflammatory mediators by disproportionate synthesis of inflammatory mediators. This signaling occurs behind an intact blood–brain barrier, similar to the blood‐labyrinth barrier in the cochlea. Local tissue damage can occur as the result of mediator release by activated macrophages. Damage is typically localized; however, if it is to structures with limited ability to repair, such as neurons or hair cells within the cochlea, it is feasible that this contributes to the progressive loss of function seen in hearing loss. We propose that macrophages in the cochlea link risk factors and hearing loss. Injury to the cochlea causes local macrophage activation that typically resolves. However, in susceptible individuals, some macrophages enter a primed state. Once primed, these macrophages can be further activated, as a consequence of circulating inflammatory molecules associated with common co‐morbidities. Hypothetically, this would lead to further cochlear damage and loss of hearing. We review the evidence for the role of tissue‐resident macrophages in the cochlea and propose that cochlear macrophages contribute to the trajectory of hearing loss and warrant further study.

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

“…A second populace derived from the FL, which is Csf1 receptor-independent, is observed in the modiolus and the intraluminal surface of the perilymphatic area inside the embryonic cochlea ( 24 ). Cochlear Mφs and perivascular macrophage-like melanocytes (PVM/Ms) lie close to blood vessels in the adult cochlea ( 33 )—such as in the cochlear modiolus, supporting cells, spiral ganglion neurons (SGNs), stria vascularis (SV), and spiral ligament (SLi)—under normal conditions ( 4 , 24 , 25 , 31 , 32 , 34 – 36 ) ( Figure 3 ).…”

“…Cochlear Mφs persist from the early post-natal stages and renew or preserve their populace via the infiltration of circulating monocytes ( 34 , 37 , 38 ). PVM/Ms are found adjacent to the blood vessels in the SV and support cells in the cochlea ( 35 , 39 ).…”

“…Although the relationship between AIED/autoinflammatory diseases and cochlear monocytes/Mφs remains largely unknown, previous studies have indicated that cochlear Mφs play crucial roles in the onset and progression of infection after insults to the cochlear sensory epithelium. Such insults include noise or drug exposure and mechanical or surgical injury to the cochlea, such as that occurring during cochlear implantation ( 5 , 31 , 34 , 62 – 72 ). These signals activate resident cochlear Mφs, switching them to a pro-inflammatory state and causing them to release cytokines that recruit monocytes into the cochlea ( 34 , 62 ).…”

“…Such insults include noise or drug exposure and mechanical or surgical injury to the cochlea, such as that occurring during cochlear implantation ( 5 , 31 , 34 , 62 – 72 ). These signals activate resident cochlear Mφs, switching them to a pro-inflammatory state and causing them to release cytokines that recruit monocytes into the cochlea ( 34 , 62 ). Infiltrating monocytes then differentiate into macrophages within the cochlea, following which they exert phagocytotic functions ( 69 , 73 ), produce inflammatory mediators, and play roles in antigen presentation ( 34 ).…”

“…These signals activate resident cochlear Mφs, switching them to a pro-inflammatory state and causing them to release cytokines that recruit monocytes into the cochlea ( 34 , 62 ). Infiltrating monocytes then differentiate into macrophages within the cochlea, following which they exert phagocytotic functions ( 69 , 73 ), produce inflammatory mediators, and play roles in antigen presentation ( 34 ). In some patients with Ménière's disease, high levels of IL-1β and TNF-α suggested that it was a chronic inflammatory disorder ( 74 ).…”