Innate Immunity to Spiral Ganglion Neuron Degeneration

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PROJECT SUMMARY Spiral ganglion neurons (SGNs), the primary afferent neurons in the cochlea, play vital functions in normal hearing by transmitting auditory information from the mechanosensory hair cells to the brain, and in restoration of hearing via cochlear implants in deaf individuals. However, exposure to traumatic and/or prolonged noise causes degeneration and subsequent loss of SGNs and their synaptic connections with hair cells in varied degrees, leading to degradation of auditory information, and impeding the performance of cochlear implants or future hair cell or synapse regeneration strategies. The reasons for such SGN degeneration remain unclear. To inform the development of novel therapies to preserve or regrow functional SGNs, it is critical to understand the biological mechanisms of SGN degeneration and survival in the injured cochlea. We have recently identified fractalkine signaling (CX3CL1-CX3CR1) between SGNs (which express chemokine CX3CL1 ligand) and innate- immune cells such as macrophages and monocytes (which express cognate CX3CR1 receptor) as a key neuroprotective signaling that promotes SGN survival and synapse repair in the injured cochlea. Here, we seek to examine the cellular and molecular mechanisms by which fractalkine signaling mediates neuroprotection in mouse cochleae following graded noise trauma. Specifically, Aim 1 will determine the precise roles of CX3CR1- expressing cochlear resident and blood-derived recruited macrophages in SGN survival or degeneration after noise trauma. Using fate mapping to distinguish and selectively deplete cochlear resident and recruited macrophages, we will test the hypothesis that CX3CR1-expressing recruited macrophages promote SGN survival after noise trauma. Aim 2 will determine whether CX3CR1 regulates macrophage responses after noise trauma such that absence of CX3CR1 results in an increased and sustained production of pro-inflammatory cytokines and reactive oxidative factors that is detrimental for SGN viability. Effector pro- and anti-inflammatory cytokines, and reactive oxygen and nitrogen species will be detected in both cochleae and macrophages with intact fractalkine signaling and those that lack CX3CR1 after noise trauma. Aim 3 will examine the relationship between human CX3CR1 polymorphisms and noise-induced hearing loss. Approximately 25-30% humans carry two single nucleotide polymorphisms (SNPs) in the CX3CR1 locus (hCX3CR1-I249/M280) that show defective binding to CX3CL1 ligand and loss of chemotactic function in macrophages. Using a novel humanized mouse model expressing the aforementioned human CX3CR1 SNPs, we will test the hypothesis that dysregulated macrophage responses due to impaired CX3CR1 signaling in these variants accelerates synapse and neuron loss and worsens hearing following noise trauma. Together, these studies will test fundamentally new hypotheses proposing specific elements of the innate immune system, macrophages and fractalkine signaling as critical targets for neuroprotective immunotherapies to promote synapse repair and SGN survival in an injured cochlea.