Interactions between Macrophages and the Sensory Cells of the Inner Ear

Abstract

Macrophages are present in most somatic tissues, where they detect and attack invading pathogens. Macrophages also participate in many nonimmune functions, particularly those related to tissue maintenance and injury response. The sensory organs of the inner ear contain resident populations of macrophages, and additional macrophages enter the ear after acoustic trauma or ototoxicity. As expected, such macrophages participate in the clearance of cellular debris. However, otic macrophages can also influence the long-term survival of both hair cells and afferent neurons after injury. The signals that recruit macrophages into the injured ear, as well as the precise contributions of macrophages to inner ear pathology, remain to be determined.

Figure 1.

Macrophages in cross sections of normal and injured cochleae. Images in A and B are frozen sections of cochleae from CX3CR1^+/GFP transgenic mice, which express green fluorescent protein (GFP) (green) in all macrophages, monocytes, and microglia. Sections were also labeled with DAPI (blue). (A,C) The uninjured cochlea contains resident macrophages, which are distributed throughout the nonsensory supporting tissues. (B,D) After loss of cochlear hair cells, increased numbers of macrophages are present in all regions of the cochlea. Arrows indicate locations where macrophage numbers are particularly enhanced after acoustic trauma or aminoglycoside ototoxicity: (I) lateral wall, (II) osseous spiral lamina, and (III) the spiral ganglion.

Figure 2.

Distribution of macrophages in the vestibular organs of mice. Shown are whole mount images of the utricle (A,A′) and horizontal cristae (B,B′) of CX3CR1^+/GFP transgenic mice, in which macrophages express green fluorescent protein (GFP) (green). Sensory epithelia are also labeled with phalloidin (red). (A,B) Moderate numbers of macrophages are present in the uninjured utricle and cristae, but are confined to the stromal/connective tissue, below the sensory epithelium. (A′,B′) Injection of diphtheria toxin in Pou4f3-huDTR mice results in the loss of most sensory hair cells, and this is accompanied by an increase in macrophage numbers in the maculae and cristae. (C) Macrophages enter the vestibular sensory epithelia after hair cell injury, where they are observed contacting and engulfing hair cell debris (arrows, C). Labels in C: green, GFP (macrophages); red, otoferlin (hair cells).

Figure 3.

Macrophage interactions with lateral line neuromasts in larval zebrafish. Transgenic fish lines in which macrophages express fluorescent proteins (e.g., mpeg1: green fluorescent protein [GFP]) permit the observation of macrophage activity in living fish. Published data show that neuromasts of the posterior lateral line typically possess one to two macrophages within a 50 µm radius of each individual neuromast (Hirose et al. 2017). Images show macrophages near the two most-posterior neuromasts of the zebrafish lateral line at 5 days postfertilization (see red box in top schematic). Macrophages are commonly observed near neuromasts in fish with intact hair cells (Control). However, injury to neuromasts by application of kainic acid ([KA], 300 µm for 1 h) or neomycin (50 µm for 30 min) causes macrophages to enter neuromasts and contact both injured hair cells and their neurons. Labels: green (GFP, macrophages), red (HCS-1, hair cells), blue (ZN-12, afferent neurons).