Macrophage Response to Otic Pathology

点击翻译按钮获取中文摘要

The senses of hearing and balance are mediated by the cochlea and vestibular organs of the inner ear. In these organs, mechanical motion (generated either by sound vibrations or by head movements) is detected by sensory hair cells and transmitted to the brain by the auditory and vestibular nerves. Hair cells are essential for sensory function, but can be injured by noise exposure, ototoxicity or infections, and are also lost as a consequence of normal aging. After injury, the timely removal of cellular debris from the sensory epithelium helps promote repair and homeostasis. This process is mediated by two distinct cell types: (1) Supporting cells, which can engulf cellular debris and – in nonmammalian vertebrates – generate replacement hair cells, and (2) Macrophages, which are effector cells of the innate immune system that also recognize and engulf dying cells. Supporting cells are present in all hair cell-containing epithelia. The tissues of the inner ear also contain resident populations of macrophages, and macrophage-mediated inflammation occurs after most types of otic injury. When responding to hair cell injury, it is critical that both supporting cells and macrophages correctly distinguish between healthy and dying cells, and then target and remove only those cells that are irreversibly damaged. A key objective of this project is to understand how this process occurs. One set of experiments will examine a signaling pathway known to be essential for evoking phagocytic responses in macrophages and other cell types, but has not been previously studied in the inner ear. In addition, we will determine whether inhibiting phagocytosis after acute injury may permit some damaged hair cells to survive, and whether the engulfment of injured hair cells is an important trigger for sensory regeneration. Studies will employ both mammalian and zebrafish models, in order to best utilize the unique advantages of both systems. A second set of experiments will enhance our very limited knowledge of the role of inflammation in the vestibular organs. Projects will focus on two clinically relevant situations. First, it is known that prenatal infection with cytomegalovirus (CMV) can cause developmental deficits in both hearing and balance, but the underlying mechanisms are completely unknown. Using a validated mouse model, we have shown that CMV infection leads to a massive inflammatory response in the vestibular maculae, which is accompanied by phagocytosis of sensory cells. We will determine whether this inflammation is the cause of CMV-induced pathology and also whether macrophages transport CMV into the vestibular periphery. Additional studies will characterize vestibular injury and inflammation in a mouse model of cochlear implantation. Completion of the studies will greatly enhance current knowledge of the cellular signals that regulate inflammation in the inner ear. Such knowledge will permit development of methods for modulating such inflammation, so as to reduce pathology and enhance functional recovery after injury.