Cochlear Immune Response in Presbyacusis: a Focus on Dysregulation of Macrophage Activity

Abstract

Age-related hearing loss, or presbyacusis, is a prominent chronic degenerative disorder that affects many older people. Based on presbyacusis pathology, the degeneration occurs in both sensory and non-sensory cells, along with changes in the cochlear microenvironment. The progression of age-related neurodegenerative diseases is associated with an altered microenvironment that reflects chronic inflammatory signaling. Under these conditions, resident and recruited immune cells, such as microglia/macrophages, have aberrant activity that contributes to chronic neuroinflammation and neural cell degeneration. Recently, researchers identified and characterized macrophages in human cochleae (including those from older donors). Along with the age-related changes in cochlear macrophages in animal models, these studies revealed that macrophages, an underappreciated group of immune cells, may play a critical role in maintaining the functional integrity of the cochlea. Although several studies deciphered the molecular mechanisms that regulate microglia/macrophage dysfunction in multiple neurodegenerative diseases, limited studies have assessed the mechanisms underlying macrophage dysfunction in aged cochleae. In this review, we highlight the age-related changes in cochlear macrophage activities in mouse and human temporal bones. We focus on how complement dysregulation and the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 inflammasome could affect macrophage activity in the aged peripheral auditory system. By understanding the molecular mechanisms that underlie these regulatory systems, we may uncover therapeutic strategies to treat presbyacusis and other forms of sensorineural hearing loss.

Keywords: Auditory nerve; Complement system; Macrophages; NLRP3 inflammasome; Presbyacusis; Stria vascularis.

Fig. 1

Location of macrophages in multiple areas of adult human cochlea. (a) IBA1⁺ macrophages are present in the auditory nerve (the eighth nerve; AN) within the osseous spiral lamina (OSL) and modiolus, and within the spiral ganglion (SG). IBA1-expressing cells are also located in the organ of Corti (arrows), within the stria vascularis (SV) and the outer sulcus and root cell (RC) regions, below the basilar membrane (M), and in the scala vestibuli on the surface of the bone (arrowheads). Images in (a) and (e) were modified from O’Malley et al. . (b) IBA1⁺ cells are present in the SV and spiral ligament of the cochlear lateral wall in a whole-mount preparation. The images of a single macrophage on the right were taken from the suprastrial (I), strial (II), and substrial (III) regions. (c, c″) A super-resolution image of a macrophage within the SV showing a three-dimensional version of macrophages with ramified processes in the strial region. Images in (b, c, c″) were modified from Noble et al. . The image in c″ is the enlarged image of the boxed area in c. (d, d”) An IBA⁺ macrophage within the SV was stained for major histocompatibility complex class type II (MHCII). The image in d″ is the enlarged image of the boxed area in d. Nu, nucleus. Images in (d, d″) were modified from Liu et al. (2019a, 2019b). CD68⁺ (e) macrophages in the SV within the intermediate cell layer (*) show ramified processes (arrows). The specimen in (b, c, c″) was obtained from a 57-year-old donor. Specimens in (a, e) were from donors ranging from 52 to 88 years old. Specimens in (d, d″) were from donors aged 40 to 70 years. BV blood vessel

Fig. 2

Age-related morphological changes in macrophages in the stria vascularis of mouse and human cochleae. The schematic (the top panel) shows two forms of macrophages (Davis et al. 1994). (a) Strial microvasculature (CD31+ endothelial cells, red) and GFP+ macrophages (green) in young adult and aged CX3CR1-GFP mice show macrophage pathology and their abnormal spatial relationships to the microvasculature. Images were taken from whole-mount preparations of the stria vascularis (SV). (b) Morphometric analysis of strial macrophages reveals significantly reduced volume and area in aged (n = 45) versus young-adult (n = 28) CX3CR1-GFP mice; *p < 0.01 (Student’s unpaired t-test). (c) Aged-related morphological alterations of macrophages in the spiral ligament (SpL) from tissues of CX3CR1-GFP mice. The macrophages were randomly selected from the whole-mount preparations of the spiral ligaments from young-adult and aged animals. (d) Strial macrophages from sections of human temporal bone show age-related changes like those seen in aged mice in (a). Age of donor is indicated in white at the top. Scale bars in (µm) = 20. Images in d were modified from Noble et al (2019)

Fig. 3

Schematic of the three pathways of the complement system that converge on C3 to activate macrophages. The classical and lectin pathways involve cleavage of C4 and C2 to make C3 convertase. Activation of C3 induces production of the cleavage products C3a and C5a, which promote inflammation. The alternative pathway can spontaneously act on C3b through Factor B (FB) in a feedback loop. Activation of C3 and the terminal pathway ultimately leads to formation of the membrane attack complex (MAC) and cell lysis. Binding of C3a and C5a with their specific receptors on macrophages triggers release of pro-inflammatory signaling molecules, leading to macrophage activation

Fig. 4

Schematic of NLRP3 inflammasome activation associated with macrophages in presbyacusis. During aging, many pathological factors (e.g., TRL4) can evoke expression of Gal-3. Gal-3 then activates NFκB through a positive-feedback loop. Also, the presence of extracellular DAMPs and PAMPs triggers lysosomal damage as shown by Gal-3 aggregation on ruptured lysosomes. Furthermore, Gal3 prevents clearance of ruptured lysosomes and enhances generation of NLRP3 inflammasomes. Furthermore, NLRP3 inflammasomes can be activated by K⁺ efflux via binding the P2X7 receptor. K⁺ efflux leads to mitochondrial damage and ROS production, critical elements of inflammasome assembly. Activation of NLRP3 inflammasomes leads to maturation of IL-1β and IL-18, and activation of caspase 1. This pathway results in chronic neuroinflammation that may contribute to the degeneration of cochlear cells and presbyacusis