While the presence of the immune system in virtually all organ systems is widely recognized, little attention has been paid to the influences of immunity on the inner ear. Research in human subjects demonstrates that hearing loss is successfully treated with corticosteroids in some patients, presumably due to their anti-inflammatory and immunosuppressive effects. Unfortunately, we possess limited knowledge of the cellular mechanisms that influence interactions between inflammatory processes and normal function of the inner ear. Because steroid therapy provides such hope for successful treatment of hearing loss, the specific mechanisms of how inflammation affects hearing warrant further study. The long-term goal of our research is to identify the role of inflammation in cochlear maintenance and injury. In prior work, we have demonstrated that hair cell injury evokes a strong, rapid recruitment of professional phagocytes in the form of monocytes and macrophages into the mouse cochlea. The present studies will use novel pharmacological methods and knockout mouse strains to examine the role of macrophages in cochlear pathology and recovery from injury. In the first set of experiments, we use liposomally-encapsulated clodronate to deplete cochlear macrophages in vivo, in order to determine whether recruited macrophages are protective or detrimental in cochlear injury. Next, we will examine the role of the chemokine receptor CX3CR1, expressed in cochlear monocytes and macrophages, in ototoxic injury. Our studies have shown that genetic deletion of CX3CR1 leads to both increased macrophage entry into the cochlea and enhancement of ototoxic injury. Proposed experiments will determine whether suppressing macrophages in CX3CR1-knockout mice can reverse this effect. Additional studies will examine the involvement of the cardinal scavenger receptor, CD36, in the phagocytosis of injured hair cells. We have shown that CD36 is expressed by both cochlear macrophages and cochlear supporting cells, suggesting that both cell types may be involved in phagocytosis of hair cell debris. We will use CD36 knockout mice to determine whether CD36 is essential for the recognition and removal of apoptotic hair cells from the organ of Corti. We will also use radiation bone marrow chimeras to isolate the effects of CD36 expression on leukocytes versus cochlear supporting cells. A final experiment will examine the dynamic role of macrophages in ototoxicity by time lapse confocal imaging of the live mouse cochlea in culture. Using this technique, we can follow the movement and activity of macrophages to determine how they interact with hair cells in ototoxic injury. These experiments will broadly study the role of leukocytes in the inner ear after hair cell injury and will allow us to begin understanding how immunosuppression affects normal processes as well as pathological processes in the inner ear.
After various forms of injury, the inner ear degenerates and inflammatory cells exit the blood vessels and enter the cochlea. To what degree these inflammatory cells could be helpful for repair or could serve to exacerbate injury is uncertain. We will use methods to suppress monocytes and macrophages, important cellular components of inflammation, to determine how these cells affect injury in the inner ear after exposure to ototoxic medications.
|Salt, Alec N; Hirose, Keiko (2018) Communication pathways to and from the inner ear and their contributions to drug delivery. Hear Res 362:25-37|
|Hirose, Keiko; Rutherford, Mark A; Warchol, Mark E (2017) Two cell populations participate in clearance of damaged hair cells from the sensory epithelia of the inner ear. Hear Res 352:70-81|
|Hirose, Keiko; Hartsock, Jared J; Johnson, Shane et al. (2014) Systemic lipopolysaccharide compromises the blood-labyrinth barrier and increases entry of serum fluorescein into the perilymph. J Assoc Res Otolaryngol 15:707-19|
|Hirose, Keiko; Li, Song-Zhe; Ohlemiller, Kevin K et al. (2014) Systemic lipopolysaccharide induces cochlear inflammation and exacerbates the synergistic ototoxicity of kanamycin and furosemide. J Assoc Res Otolaryngol 15:555-70|
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|Hirose, Keiko; Sato, Eisuke (2011) Comparative analysis of combination kanamycin-furosemide versus kanamycin alone in the mouse cochlea. Hear Res 272:108-16|