Csf1 Signaling Regulates Maintenance of Resident Macrophages and Bone Formation in the Mouse Cochlea.

Ippei Kishimoto,Takayuki Okano

doi:10.3389/fneur.2019.01244

Abstract

In the mammalian cochlea, resident macrophages settle in the spiral ligament, spiral ganglion, and stria vascularis, even at the steady state. Resident macrophages in the cochlea are believed to maintain homeostasis in the inner ear and become active, as part of the front line defense, following inner ear damage. However, the exact roles of cochlear resident macrophages require further clarification. Colony stimulating factor-1 (Csf1) signaling regulates survival, proliferation, and differentiation of resident macrophages and appears to be essential for resident macrophages in the inner ear. To examine the roles of Csf1 signaling in auditory function, we examined the ossicles and inner ear of homozygous Csf1 mutant (Csf1op/op) mice. The ossicles including the incus and stapes of Csf1op/op mice macroscopically demonstrated bone thickening, and the otic capsules of the inner ear were also thick and opaque. Histological analyses demonstrated that the otic capsules in Csf1op/op mice were thickened and showed spongy bone degeneration. Measurements of the auditory brainstem response revealed significant elevation of thresholds in 4-week old Csf1op/op mice compared with wild-type littermates, indicating that Csf1op/op mice demonstrate hearing loss due to, at least in part, deformity of the ossicles and bone capsule of the inner ear. Furthermore, Csf1op/op mice are deficient in the number of resident macrophages in the spiral ligament and stria vascularis, but not in the spiral ganglion. These data provide evidence that Csf1 signaling is important not only for bone formation in the inner ear, but also for the maintenance of resident macrophages in the spiral ligament and stria vascularis in the adult mouse cochlea.

Highlights

The inner ear was once believed to be “immune-privileged,” because the concentration of IgG in the perilymph is as low as in the cerebrospinal fluid and there is no lymphatic drainage or lymphoid tissue
The obturator foramen of the stapes pierced by the stapedial artery was smaller in Csf1op/op mice compared with wild type (WT) littermates due to excessive bone formation of the stapes (Figures 1F,G)
The latencies of waves I and III were consistently delayed in Csf1op/op mice without any lengthening of interval between waves I and III, potentially suggesting conductive hearing loss in Csf1op/op mice. These findings suggest that moderate hearing loss shown in Csf1op/op mice was due to, at least in part, deformity of the ossicles and the otic capsule leading to a conductive hearing disorder, the possibility of mixed hearing loss cannot be completely excluded

Summary

Introduction

The inner ear was once believed to be “immune-privileged,” because the concentration of IgG in the perilymph is as low as in the cerebrospinal fluid and there is no lymphatic drainage or lymphoid tissue. Previous studies have demonstrated the presence of immune-competent cells in specific parts of the inner ear such as the spiral ganglion and the spiral ligament, which are referred to as resident macrophages in the cochlea [2, 3]. Tissue resident macrophages are distributed in virtually all organs and tissues in the body and provide crucial innate immune defense and tissue-specific functions in the regulation and. Macrophages acquire inflammatory effector functions, but they can develop regulatory properties essential for tissue protection and repair. Cochlear resident macrophages are thought to be important for the immune system of the inner ear, including maintenance of the local environment and repair of damaged tissue or cells. Many aspects regarding the functions of cochlear macrophages remain to be elucidated

Methods

Results

Conclusion